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SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.
Genetics & Mendel’s Principles
G
Geenneettiiccss

It is a common experience and perception of humans that offspring of plants,
animals and our own species look similar, but not identical, to their parents; some
traits and characteristics, such as height of a plant, flower color, fur color, skin color
and ear shape, must have been passed on to the next generation by some form of
information carrier

Today, we know that these biological information carriers are genes located on
chromosomes which are passed on to the next generation in a process called
heredity
- it is the genes which build the information units of the biological program of living
organisms
- each gene of a biological organism codes for a distinctive protein that itself
contributes to a specific biological function within a cell

the term Genetics which derives from the word “genes” is a relatively young and
very dynamic sub-discipline of Biology
- the term “genetics” was introduced by the English biologist William Bateson
(1861-1926) in 1906 to name a new discipline of biology
- with genetics he meant the scientific study of heredity, a term which refers to the
similarity between genealogically related organisms, e.g. parents and children,
first and second degree cousins, etc.

Genetics is the scientific study of heredity of living organisms; i.e. the passing on
of characteristics from parents to their offspring
 geneticists study how the smallest units of heredity – the genes –
are passed on from one generation to the other

the science of genetics came a long way in human history which is paved by the
names of one of the most brilliant minds of biological science
H
Hiissttoorryy ooff ggeenneettiiccss
A
Anncciieenntt G
Grreeeeccee: H
Hiippppooccrraatteess suggested the idea of Pangenesis to explain heredity
 according to this hypothesis, genes travel from one body to the
sperms and eggs of another body
E
Eaarrllyy 1199ttthhh cceennttuurryy: Jean-Baptiste P. A. de Lamarck (1744-1829) states the so-called
blending hypothesis which dominated the scientific thoughts about heredity
 according to his hypothesis, hereditary traits of each
parent are mixed (= blended) to form a novel trait in the
offspring
 he also stated that acquired characteristics are inherited
1
SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.
E
Eaarrllyy 11886600ss: the Austrian Augustinian monk Johann Gregor Mendel (1822-1884)
observes that certain traits of the garden pea are inherited by (as he called it by that
time) heritable factors in a defined and predictable way  he writes his famous
“Principles of genetics” (1865)
11887766:: Horner, a British physician recognizes for the first time red-green color
blindness as a "sex-linked" inherited disease
 he observed in that color blindness is inherited in boys from
mothers whose brothers had the problem
11887799//11888888:: The scientists Flemming (1879) and Strasburger (1888) observe the
movement of chromosomes in mitosis and meiosis, respectively, but do not see the
connection to inheritance
11889922:: the German biologist August Weismann proposes that chromosomes play a
central role in heredity
11990000:: K. Correns, F. Tschermak & H. DeVries rediscover Mendel’s earlier stated
inheritance patterns in plants; discovery of incomplete inheritance patterns as an
important variation to Mendel’s genetic principles
A
Arroouunndd 11990022:: the systematic analysis of Mendelian inheritance patterns in plants,
animals and human begins
eeaarrllyy 11990000ss: the Dutch botanist H. de Vries observed and described unexpected
differences in characteristics of offspring which were caused by changes in the genes
 he called these gene changes mutations
11990099:: the Danish biologist Wilhelm Johannsen (1857-1927) introduces the term
“gene” into the scientific literature
A
Abboouutt 11991100:: the American biologist Thomas H. Morgan (Rockefeller University, New
York) discovers that the genes responsible for heredity are located on cell structures
called chromosomes; introduction of the chromosomal theory of inheritance
- he concluded from crossing experiments with the fruit-fly Drosophila that genes
occasionally cross-over from one chromosome to another and give rise to new
trait combinations
- careful examination of the frequency of recombinants in Drosophila leads to the
first mapping of certain genes on chromosomes  begin of chromosome
mapping in genetics
11992277:: The American geneticist H.J. Mueller proves that X-ray beams cause DNA
mutations and he determines the spontaneous mutation rate in the genome of
Drosophila flies
eeaarrllyy 11994400ss: the American geneticists G. W. Beadle & E. L. Tatum discover in the
fungus Neurospora crassa, that one gene controls the expression of one enzyme; “one
2
SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.
gene – one enzyme hypothesis” ; some genes control the production of enzymes 
genetic control of protein expression!
11994400ss: scientists discover that genes are segments of DNA; DNA is recognized as the
blue-print molecule of heredity
11994499:: Neel discovers sickle cell anemia as a heritable disorder in humans and
Pauling, Itano, Singer & Wells show that the disorder is due to a mutation of the red
blood cell protein hemoglobin
11995522:: Carl F. Cori & Gerty T. Cori and others discover the hereditary nature of
several metabolic disorders (glucose-6-phosphate deficiency, glycogen storage
disease) in humans; the era of human genetics begins
11995533:: F. Crick & J. Watson describe the molecular structure of the genetic material;
they state that the hereditary molecule DNA forms a double helix, in which the four
bases adenine, guanine, cytosine and thymine are base-paired following the famous
“Watson-Crick base-pairing rule”
 the modern understanding of DNA replication and of molecular biology begins
LLaattee 11996600ss:: the scientists Stewart Linn and Werner Arber isolate for the first time a
restriction endonuclease, an enzyme responsible for phage growth restriction in
Escherichia coli and which cleaves DNA at a wide variety of locations along the length
of the molecule
 the era of genetic engineering begins
11996600ss aanndd 7700ss: scientists discover more enzymes which are able to cut DNA or glue
DNA strands together; they also discover extra-chromosomal DNA, called plasmids, in
bacteria, which soon become successfully exploited as important ‘tools’ in a new
discipline called genetic engineering
 genetic engineering becomes one of the most valuable and exciting
tool in genetic research and ‘biotechnology’
11997700ss:: P. Duesberg & P. Vogt discover the first oncogene, a gene which is implicated
in many human cancers.
A
A.. LLeevviinnee,, LL.. C
Crraaw
wffoorrdd &
&D
D.. LLaannee discover p53, the gene most commonly mutated in
human cancers
TTooddaayy:: American and European research teams read the complete DNA sequence of
the human genome (all 6,000,000,000 DNA base pairs in our cell nucleus !!)
- the detailed knowledge about the DNA sequence and location of individual
genes on the human chromosomal material holds the great promise to open the
door to a better understanding and diagnostics of human genetic diseases
- to the scientists surprise, the human genome contains less genes than expected;
only about 40,000 genes
3
SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.
Genetic Terminology

before we are going into more details and try to understand the principles and
intricate mechanics of inheritance, we first must make ourselves familiar with the
terminology as it relates to genetics and heredity

Inheritance, i.e. the passing on of heritable traits in biological organisms, has a lot to
do with genes, alleles, chromosomes, meiosis, breeding, genotype and phenotype
1. Trait:
 A variant of a character, e.g. purple or white flower, yellow or green seed
2. Character:
 An inherited characteristic of a biological organism, e.g. skin color, flower
color, seed color, stem length
3. Gene:
 an approx. 500 – 1000 base-pair long segment of the DNA molecule that is
responsible for the manufacturing (= synthesis) of a protein ( s. protein
translation)
 the protein may be either become a part of the organisms structure or
become an enzyme responsible for the control of biochemical events in the
cell
 every gene has a unique location (= locus) on a distinct chromosome, which
can be unraveled by a scientist using a process called genetic mapping
 today, the location of many genes on the 46 human chromosomes has been
pin-pointed by geneticists, but gene mapping is an ongoing task in modern
molecular genetics
4. Chromosome
 long DNA fragment as part of the total cellular DNA (=genome) that heavily
folds and coils up into the typical X-shaped and visible chromosome form
during cell division and meiosis
 every biological organisms has its genomic DNA fragmented into a definite
number of chromosomes
 the otherwise non-visible chromosomes are called chromatin (= DNA plus
proteins)
5. Homologous chromosomes
 are the pairs of identical shaped and sized chromosomes in the cells of
more complex, diploid organisms
 they are the result of sexual reproduction after fusion of male and female
haploid gametes, each having only one set of chromosomes, to form a new,
diploid organism
 diploid organisms have two of each kind of chromosomes; they have two
complete sets of homologous chromosomes
 since genes are located on chromosomes, diploid organisms have two of
each kind of genes located on the same loci on the homologous
chromosomes
4
SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.
6. Alleles
 are alternate forms of a particular gene located on the identical locus on
either homologous chromosome in the cells of diploid organisms
 each allele is contributed from a different (maternal or paternal) individual
 allele pairs have the genetic information for the same trait and are located at
the exact same spot on homologous chromosomes
 but since each allele originated in a different individual it does not have the
exactly identical gene (sequence); it has slight DNA variations due to
mutation events
7. Genotype
 is the description of the alleles an individual possesses for a particular trait
has on its homologous chromosomes
 usually written as a one-letter code, e.g. YY or AB
 for many (not all) genetic characters or alleles there are 3 possible genotypes;
e.g. the “K” allele may appear in the cells of a biological organism as KK, Kk
or kk genotype
 if an organism has two identical alleles “A” or “a” located on its homologous
chromosomes, we call this organism homozygous for that specific trait, e.g.
AA or aa
 if an organism has two different alleles, C and c, located on its homologous
chromosomes, we say that it is heterozygous for that trait, or annotated Cc
8. Phenotype
 the physical (= body/tissue/cell) expression of the genetic information of
the alleles of a biological organism
 since there are different possible combinations of alleles (2 sets in a diploid
organism!), there are alternative possible phenotypes for a particular trait
TThhee rruulleess ooff ggeenneettiiccss ((oorr M
ME
EN
ND
DE
ELL’’S
SP
PR
RIIN
NC
CIIP
PLLE
ES
S))

the beginning of our modern understanding of heredity and inheritance patterns we
owe the tedious and ingenious breeding experiments of an Austrian monk named
Gregor Mendel (see Figure below), which disproved Lamarck’s “blending theory of
inheritance”; in 1866 he publishes his experimental findings he retrieved while
working with the common garden pea (Pisum sativum) in form of a scientific paper in
a relatively unknown scientific journal
- the famous, almost forgotten paper with the German title “ Experimente zur
Pflanzenhybridisierung “ (“experiments in plant hybridization”) which he wrote in
1866 became the foundation for modern genetics and inheritance
- although Mendel never lived to see it, the experiments and conclusions in his
published paper were revolutionary and build today the foundation of “Mendelian
genetics” and are summarized in the famous Mendelian principles or Mendel’s
laws of genetics
- if you’d like to read Mendel’s paper (translated into English), it can be found on
the Internet under following web address:
http://www. mendelweb.org/Mendel.html
5
SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.
Gregor Mendel: The founder of modern genetics
Johann Gregor Mendel
(1822 – 1884)
Augustinian monk,
teacher & scientist
Old Brno monastery with Mendel’s green house
where he conducted his famous breeding experiments in the
1850s with the common garden pea

Mendel’s greatest contribution to science was to disprove the (at his time
predominant) “blending theory of inheritance”, a theory which was introduced in the
early 1800s by the Frenchman J.B. Lamarck
- according to the blending theory, all heritable traits blend with each other in the
next generation

Mendel however showed that genes, the DNA-made master instructors of traits in
biological organisms, do not blend in the next generation, rather they are passed on
6
SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.
to the next generation as discrete “units of heredity”, as (according to modern
terminology) genes
“Mendel revolutionary contribution to science was that he replaced the
blending theory with the particulate theory of inheritance … “

Mendel’s particulate theory of inheritance states:
1. inherited characters are determined by particulate factors (today called
genes)
2. the particulate factors in sexually reproducing organisms occur in pairs in
alternate version called alleles (today we know that these alternate gene
pairs are located on homologous pairs of chromosomes each inherited from
one of the biological parents)
3. when gametes form, the alleles (gene pairs) segregate so that only one of
each allele (gene) ends up in each gamete, i.e. sperm or egg cell

one of the keys to Mendel’s experimental success which led to the discovery of the
particulate theory of inheritance was the wise (or fortunate?) decision to chose the
common garden pea (Pisum sativum) as his “model organism” to conduct his
famous breeding experiments
 his experiments led to the discovery of the fundamental principles of genetics
and marked the beginning of the era of modern genetics

The garden pea had a series of favorable features which were largely responsible
for Mendel’s experimental success
1. it is easy to grow and is available in many readily distinguishable varieties
 e.g. blossom color, seed shape, pod color, etc. (see Figure below)
2. he could exercise strict control over plant matings by switching between the
natural process of self-fertilization and the experimental procedure of cross
fertilization
 he was able to control the parentage of the new plants
3. he could select from a series of easy-to-follow plant characteristics (see
graphic)
 Mendel chose seven of these characteristics, i.e. flower color,
flower position, seed color, seed shape, pod shape, pod color
and stem length for his breeding studies
4. he diligently worked with his plants and plant characteristics, until he could be
sure to have so-called true-breeding varieties
 a true-breeding variety is a variety for which self-fertilization produced
offspring all identical to the parent
 with his true-breeding varieties he performed his famous
breeding experiments to generate hybrids
 hybrids are the offspring of two different, true-inbreed varieties
7
SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.
Easy distinguishable traits in the garden pea

the cross fertilization of two true-inbred parental plants (= P generation) to generate
hybrid offspring (= F1 generation) is also called hybridization or a cross

Mendel created first an F1 generation of hybrid offspring after crossing two trueinbreed parental plants (= yellow seed-colored Parent 1 pea plant and green seedcolored Parent 2 pea plant)(see Figure below), which differed in only one trait, i.e.
seed color
Mendel’s cross between 2 true-inbred parental pea plants
Phenotype
P
P--ggeenneerraattiioonn
Genotype
FF11--ggeenneerraattiioonn
8
SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.

Mendel observed that all (= 100%) of his garden pea hybrid plants in F1
generation had only yellow, round seeds and no green seeds, mixed colors or
shapes
- this enormously significant observation strongly spoke against the (at his time
widely accepted) blending hypothesis, which has been stated earlier by J.B.
Lamarck
- the distinguishable traits he chose for his breeding experiments obviously did
not blend or mix in the following F1 generation

In the second step he self-fertilized or cross-fertilized this F1 generation and
studied the distribution of his characteristics, e.g. flower color or seed color, in
the next, so-called F2 generation

by mating the F1 plants Mendel discovered the re-appearance of the green
seed color in ¼ of all F2 plants, while the rest ¾ had yellow seed color again; he
observed his famous 3:1 pattern regarding the examined phenotypes
M
Moonnoohhyybbrriidd ccrroossss eexxppeerriim
meenntt
Cross
Plant1
Plant2
Outcome
(Offspring)

Punnett-square
9
SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.

Mendel repeated identical experiments with true-bred garden pea varieties
carrying differences in other traits, such as petal color, seed shape or pod color

He performed several of these classical so-called monohybrid crosses
 in all these experiments he tracked the inheritance of one single
characteristic of two true-inbred parent plants
 e.g. parent plants with either white or purple flower color or
parent plants with yellow or green seeds
“A monohybrid cross is a breeding experiment with a sexually
reproducing species in which the two bred individuals differ in one
distinguishable trait…”

Mendel observed identical outcomes in these monohybrid cross experiments
regarding phenotypes in F1 and F2 generations; from these identical results from
with different characteristics, e.g. blossom color or pod shape, Mendel formed 4
hypotheses, today referred to as Mendel’s Principles
 each of the seven characteristics he studied showed the same
inheritance pattern
M
Meennddeell’’ss pprriinncciipplleess
1. there are alternative forms of genes that determine heritable traits
 Mendel used the term ‘heritable factors
 each form of genetic trait is called an allele
 e.g. Y
Y for yellow seed color or yy for green seed color
2. for each inherited character or trait an organism has two alleles (genes)
 one from each biological parent
 they may be the same allele or may be different
3. Male sperm/pollen or female oocytes (eggs) carry only one allele for each
inherited trait
 Allele pairs segregate from each other during the production of
gametes in meiosis
 after fertilization of egg and sperm each allele contributes to the
paired condition in the offspring
4. When two genes of a pair are different alleles and one is fully expressed while
the other one has no noticeable effect on the organisms appearance, the
alleles are called dominant and recessive alleles, respectively
M
Meennddeell’’ss pprriinncciippllee ooff sseeggrreeggaattiioonn

in sexually reproducing biological organisms, only the trait information on one
gene (= of one the two alleles) is put into each gamete formed during meiosis
10
SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.

it states that genes or alleles segregate during gamete formation
 and fusion of gametes during fertilization pairs the genes again
These basic facts of the connection between sexual reproduction, meiosis and allele
segregation during meiosis form the basis of modern Mendelian genetics. However,
this crucial connection between Mendel’s discoveries of allele segregation and
meiosis was made more than 40 years after he published his discoveries by other
scientists, namely by Tschermak, Correns and DeVries in the early 1900s

The Figure below shows the segregation of two different alleles “S” and “s”
during meiosis and its location in different gametes
Segregation of allele pairs during meiosis
S
S = dominant allele
ss = recessive allele

if after fertilization, an organism has the genotype, e.g. S
Sss, we call this organism
heterozygous regarding the Allele ‘S’

if after fertilization an organism has the genotype S
SS
S or ssss, we call this organism
dominant or recessive homozygous regarding the Allele ‘S’ or ‘s’

Homozygous organism
 is a true-breeding organism with a pair of identical
alleles for a certain characteristic or trait
 e.g. Y
YY
Y or yyyy for the seed color of the garden pea

Heterozygous organism
 organism with two different alleles for a characteristic
 e.g. the F1 hybrids in Mendel’s experiment were all Y
Yyy,
with the dominant allele Y which carries the gene for the
yellow seed color
11
SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.
Segregation of allele pairs during
meiosis in the gonads
((ddiippllooiidd))
pre-germ cell

((hhaappllooiidd))
sperm or egg cell

Test cross
or … how could Mendel be sure to have true-inbred pea plants
homozygous for an allele?

Mendel conducted so-called test cross with his plants to determine the plant's
genotype

In a test cross, an individual with an unknown genotype (e.g. Y
YY
Y or Y
Yyy ) is
crossed to an individual with a known homozygous, recessive genotype
 in our case it would be a true-breeding pea plant with
green seeds and the yyyy genotype

Suppose you were given a pea plant with the “yellow seed” phenotype; it’s
genotype could be either one of two possibilities: either Y
YY
Y or Y
Yyy

the outcome of a test cross, means the distribution of the phenotype, will tell
about the hidden, second allele of the heterozygous individual

today, geneticist use the test cross to determine unknown genotypes in
agricultural plants or domestic animals
12
SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.
“In dominant recessive traits it is often not possible to distinguish between
individuals homozygous dominant (DD) or heterozygous (Dd) genotypes because
they would have the same phenotype. A classical way (used by Mendel in the early
days of genetics and by many life stock or animal breeders today) to determine the
(unknown) genotype of an individual with a dominant phenotype is to conduct a test
cross..”

the experimental outcome and analysis of the offspring of a test cross experiment
(see different outcome scenarios below) will reveal the unknown genotype of the
individual
TTeesstt ccrroossss oouuttccoom
meess
C
Caassee 11::
uunnkknnoow
wnn genotype: = homozygous dominant
Y
YY
Y
Y
Y
Y
Y
sperm
or
egg cells
Y
Yyy
Y
Yyy
yy
yy yy
Y
Yyy

Y
Yyy
known genotype:
yy
if the genotype of the unknown pea plant was homozygous, dominant (=
YY) regarding the trait seed color, then all of the resulting offspring (=
100%) will have yyeelllloow
w seed color
C
Caassee 22::
uunnkknnoow
wnn genotype: = heterozygous
Y
Yyy
Y
Y
yy
sperm
or
egg cells
Y
Yyy
yyyy
yy
Y
Yyy
yyyy
yy
yy yy
known genotype:
13
SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.

if the genotype of the unknown plant was heterozygous (= Yy) regarding
the trait seed color, then the outcome of the cross will be :  50% of all
offspring have yyeelllloow
w seed color; 50% have ggrreeeenn seed color

A so-called Punnett square helps to illustrate the possible combinations of
alleles of F1 gametes in the F2 generation after crossing
 it helps to visualize the genotypic distribution of alleles of one trait

Because an organisms appearance does not always reveal its genetic
composition , geneticist distinguish between an organisms phenotype (= its
outer appearance), e.g. yellow or green seed color; blue or brown eyes, and the
genotype (= its collection of genes and alleles), e.g. Y
YY
Y or Y
Yyy or yyyy
TThhee cchhrroom
moossoom
mee tthheeoorryy ooff iinnhheerriittaannccee

Mendel’s principles were not understood until cell biologists discovered
chromosomes in the early 1900s and described the intricate movements of
chromosomes during the biological processes of mitosis and meiosis in more
detail
 especially the observed parallels of the behavior of the chromosomes in both
processes with the behavior of Mendel’s heritable factors lead to the
conclusion, that:
1. the behavior of chromosomes during mitosis and meiosis accounts for the
inheritance pattern of Mendel’s factors
2. genes are located on chromosomes
 Mendel’s principle of iinnddeeppeennddeenntt aassssoorrttm
meenntt corresponds to Metaphase I of
meiosis, while Mendel’s principle of sseeggrreeggaattiioonn corresponds to M
Meettaapphhaassee IIII of
meiosis
 Alleles (= alternative forms) of a gene reside at the same locus on homologous
chromosomes
 the typical labeled bands on the chromosomes one observes in a karyogram
represent a few gene loci
 the matching colors on both homologous chromosomes (band pattern)
highlight the fact that homologous chromosomes have genes for the same
characteristics located at the same positions
 but one band is not identical with one allele but rather shows about 10-100
genes

Mendel extended his studies from monohybrid cross to so-called dihybrid cross
 he mated true-bred parental pea varieties which differed in two
characteristics
14
SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.
D
Diihhyybbrriidd ccrroossss

Mendel expanded his scientific curiosity by conducting a series of breeding
experiments with true-bred garden pea varieties which differed regarding two
heritable traits, e.g. in seed shape and seed color

He performed several of his classical so-called dihybrid cross experiments (see
Figures below)
- in all these experiments he tracked the inheritance of two characteristic of
two true-inbred parent plants (= P generation)
- e.g. parent plants with differences in seed shape (round & wrinkled) and seed
color (yellow & green)
“A dihybrid cross is a breeding experiment with a sexually reproducing
species in which the two bred individuals differ in two distinguishable
trait…”

Mendel crossed homozygous plants with dominant yellow, dominant round
seeds (= genotype: Y
YY
YS
SS
S) with homozygous plants with a recessive green,
recessive wrinkled seeds (= genotype: yyyyssss)

All (= 100%) F1 plants had round and yellow seeds in their pods, but since they
are the product of parents with two different phenotypes (regarding the studied
traits) they were hybrid plant with the genotype Y
YyyS
Sss

when he crossed two F1-generational hybrid plants with each other he observed
two new phenotypes not seen in previous generations (see Figure below); these
new phenotypes of the F2 generation he ingeniously interpreted as the
consequence of the independent assortment of the alleles responsible for the
heritable traits; his results supported the hypothesis that the genetic information
was not inherited as an “allele package”, but that each allele for each trait
segregates independently during gamete formation
15
SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.
M
Meennddeell’’ss pprriinncciippllee ooff iinnddeeppeennddeenntt aassssoorrttm
meenntt
D
Diihhyybbrriidd ccrroossss w
wiitthh ttw
woo FF11 ppllaannttss

This finding is also called Mendel’s principle of independent assortment

The principle of independent assortment applies also to the inheritance of other
dominant-recessive-inherited genetic traits in other sexually reproducing
biological organisms
- e.g. the inheritance of feather colors in budgies
 two genes are involved, each with two alleles (B and b, C and c)
 birds with B allele have yellow pigment in their feathers
 birds with C allele have dark melanin pigment which makes their
feathers blue or darkish colored
 birds with the recessive b or c allele produce no pigment and are
therefore white-feathered

Today, geneticist routinely use the core ideas of Mendel’s famous principles to
solve genetic problems involving dominant-recessive heritable traits in
different sexually reproducing organisms, from a simple yeast or algae, up to the
most complex animals, including humans

The following section outlines a detailed example describing in detail how to
solve a genetic problem involving dominant-recessive alleles
16
SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.
Example: How to solve a simple genetic problem using a Punnett square
The population of a sexually reproducing species “Z” shows tall and short members,
a distinctive trait which is inherited; from previous breeding experiments with truebred parental individuals of this species (= P-generation) you know that tallness (T)
is dominant over shortness (t); at this point you can write down:
1) The genotype of the true-bred P-generation is:
- TT
 tall parent (P1) (= homozygous dominant)
- tt
 short parent (P2) (= homozygous recessive)
2) Each parent produces gametes (sperm or egg cells) with only one
of the same allele
- P1 (TT) 
only gametes with one T allele
- P2 (tt) 
only gametes with one t allele
3) A mating between parent P1 and parent P2 will create tall F1
generational offspring which all will be heterozygous (= genotype:
Tt) regarding the body height allele
To answer the following questions regarding the prospective genotypes of
phenotypes of a mating between two F1 generational individuals of this species (F1
x F1) you follow the steps below.
1. Set up a genotype and phenotype legend to refer back to later after
completion of the Punnett square in step 4) below
Genotypes
TT
Tt
tt
Phenotypes
tall body
tall body
short body
2. Set up the cross as directed in the stated problem; here in this example a
cross between F1 (Tt) x F2 (Tt)
F1 (male)
Tall
Tt
X
F1 (female)
Tall
Tt
Phenotype
Genotype
3. Determine the kinds of gametes each individual can produce by meiotic
cell division in the gonads
Male gametes = sperm (2 types)
Female gametes = oocytes (2 types)`
T and t
T and t
4. Use a Punnett square (see below) to determine what kinds of F2generational offspring genotypes are possible when the gametes of
step 3) combine by chance during fertilization ( simulation of all random
fertilization outcomes)
17
SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.
F1
(male)
Meiosis
T
F1
(female)
T
t
TT
TtTt
Gametes
Meiosi
t
Tt
Genotype
(Offspring)
tt
Gamete
Punnett square
Phenotypes
tall
short
5. Determine the resulting F2 phenotypes based on the genotype outcomes
with the help of the table developed in step 1) above; a.) determine the
percentages for each phenotype knowing for a monohybrid cross that
each square symbolizes 25% of the total offspring (4 squares = 100%);
determine the probability p for each phenotype based on the fact that each
square symbolizes a probability p = 0.25

Use the strategy above to solve simple genetic problems involving dominant/
recessive inherited traits
TThhee rruulleess ooff pprroobbaabbiilliittyy aappppllyy ttoo M
Meennddeell’’ss pprriinncciippllee ooff iinnhheerriittaannccee

Mendel knew, due to his strong background in mathematics and statistics, that
he had to count many offspring from his crosses in order to interpret and predict
inheritance patterns; he was very familiar with the mathematical laws of
probability which are very helpful to predict the outcomes of breeding
experiments

The probability “p” scale ranges from 0 to 1
 an event that certainly occurs has the probability p of 1
18
SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.
 an event that is not expected to happen has a probability of 0
 e.g. for coins each toss has a p of ½ for head or tail
 each toss is a so-called independent event, which means
that the outcome of any particular toss is unaffected by the previous one
 p is always ½ for each toss
 p for two heads after tossing two coins is calculated by
the rule of multiplication;
p = ½ x ½ = ¼ for two heads on the table after one toss

The rules of stochastics applied to genetics means, that the probability for any
genotype can be predicted if the genotype of the parents is known
 e.g. the probability that 2 alleles come together at fertilization is ½ x ½ = ¼

the probability of a certain genotype to occur in the F2 generation, which is
heterozygous for a specific allele (Aa), can be calculated by applying the socalled rule of addition to that statistical problem
 this rule states, that the probability is the sum of the separate probabilities
 the probability for a heterozygous F2 genotype to occur is therefore:
¼ (A) + ¼ (a) = ½ (Aa)

By applying the rules of probability to chromosomal segregation and independent
assortment even complex genetic problems can be solved

E.g. the outcome of a tri-hybrid cross of two F1 individuals with three different
characteristics (= genotype: AaBbCc) can be predicted
 since each allele pair assorts independently this tri-hybrid cross
can be treated as 3 separate monohybrid crosses
 to calculate the probability of the appearance of the recessive homozygote
aabbcc, the so-called rule of multiplication is applied to solve the problem
Aa x Aa
Bb x Bb
Cc x Cc



p of aa
p of bb
p of cc
= ¼
= ¼
= ¼
P (aabbcc) = ¼ aa x ¼ bb x ¼ cc = 1/64
 the same result (with a little more effort!) could be retrieved by
construction of a 64-section Punnett square

most of the genetic traits and characteristics of an individual are encoded and
located on autosomes
 they are inherited in the typical Mendelian, dominant-recessive pattern

but many traits in biological organisms, including humans are encoded and laid
down on sex or gender chromosomes; consequently, they are inherited in a
gender or sex-linked manner (see  X-linked inheritance in the sections further
below)
19
SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.
Dominant - recessive inherited traits in humans (Human Genetics)
“Mendel’s principles apply also to the inheritance of many genetic traits
in humans”

While there is nothing unique about the genetic mechanisms occurring within our
own species, humans obviously have a high curiosity about the genetic human
traits; this becomes even more understandable if one considers the many
heritable disorders (many of which you will hear more about in this section of this
chapter) which unfortunately affect many members of our societies

human cells like the cells of the garden pea or of the cells of any other biological
organism have their genetic information encoded on genes which are located on
chromosomes

human cells also produce haploid germ cells (= sperm and oocytes) by meiosis
and reproduce by fertilization

therefore, even though human cells contain many more genes ( around 40,000 !!)
than the garden pea, heredity in humans follows the same Mendelian principles
of inheritance

indeed, many human traits are known, which are determined by simple
dominant-recessive alleles which are inherited in the same dominant-recessive
Mendelian patterns
S
Soom
mee rreecceessssiivvee oorr ddoom
miinnaanntt ttrraaiittss iinn hhuum
maannss
Trait
eye color
earlobe
dimpled chin
widows peak
bent little finger
freckles
PTC paper
finger number
hairline
Allele
ddoom
miinnaanntt
brown
free lobes
Cleft in chin
Hairline with distinct
point
Little finger slightly
bends towards 4th
finger
yes
able to taste
six
Widow’s peak
rreecceessssiivvee
blue
attached
Absence of cleft
Straight hairline
Straight little finger
no freckles
not able to taste
five
straight line
20
SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.

recessive phenotypes ‘no freckles’, straight hairline and attached earlobes,
require a homozygous, recessive genotype aa to become visible in an individual

Human traits of inheritance are much more difficult to analyze because one can
only study the result of matings (‘crosses’) that have already occurred
- in this regard it is important to collect information about the family history of
that specific trait (= genealogy) and to put this information in a so-called
family-tree – the family pedigree
- the follow-up and appearance of certain phenotypes, e.g. a specific disorder
or condition, in a given family over several generations (P, F1, F2, F3, etc.)
will give important glues about whether the trait is inherited in a dominant,
recessive, autosomal or sex-linked fashion
- the Figures below show hypothetical family pedigrees for a fictive disorder “D”
which runs in a family; the Figure below shows the appearance of disorder
“D” over generations if it is inherited in a autosomal recessive manner
 1. both gender are affected equally
 2. “D” skips one generation and reappears in the second next generation
Family pedigree for an autosomal recessive trait
male
female
P
F1
F2
Disorder “D”
Genotype:
-
dd
Disorder “D”
dd
the Figure below shows a family pedigree with an autosomal dominant
inherited disorder “D”
 1. both gender of the family are affected equally
 2. the disorder “D” affects members of the family in each generation
21
SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.
Family pedigree for an autosomal dominant trait
male
female
Disorder “D”
Genotype:
-
Disorder “D”
Dd
Dd
the allele/gene for the disorder “D” is recessive and located on the Xchromosome; it is inherited in a X-linked fashion (for more detail the sections
below)
 mostly males of the family are affected by the disorder “D”
 50% of the females of the family are carriers for the disorder
Family pedigree for the X-linked disorder “D”
male
female
“Carrier”
Genotype:

XDXd
Disorder “D”
XdY
Many inherited disorders in humans are controlled by a single gene
 more than 1000 dominant or recessive traits are known
 these traits show therefore simple inheritance patterns, which can be
described and predicted by Mendel’s principles
22
SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.

with the knowledge of Mendel’s principles and with the help of the laws of
probability, the fraction of offspring affected by a certain trait can be predicted

2 forms of heritable disorders are known in humans
II..
R
Reecceessssiivvee ddiissoorrddeerrss

are disorders which only appear in individuals who are homozygous regarding
the recessive allele (= people with an aa - genotype)

but many otherwise healthy individuals are so-called carriers of a recessive allele
which is responsible for a certain disease (they have an Aa – genotype)

Examples of recessive human disorders are:
11.. H
Heerreeddiittaarryy ddeeaaffnneessss
22.. C
Cyyssttiicc ffiibbrroossiiss
 it is the most common lethal genetic disease in the U.S.
 the responsible allele is differently distributed
amongst different ethnic groups
Probability p
1/1800
1/17000
1/90000
Caucasian Americans births
African American births
Asian American births
 a homozygous individual (= with 2 copies of the
defect CF allele) develops the disease
 the disease is characterized by excessive production/secretion of a
very thick mucus in the lungs, pancreas and other organs
33.. S
Siicckkllee cceellll aanneem
miiaa
 homozygous persons have sickled red blood cells,
which cause serious damage to many tissues in the body
 affects one out of 500 births of African-Americans;
and 1 out of 10 African Americans is a heterozygote carrier of the
sickle cell allele
 heterozygotes have a high natural resistance against Malaria
 it is a very rare disease amongst other ethnic groups
44.. A
Allbbiinniissm
m
 people lack the pigment melanin in skin, hairs and
eyes
 affected persons (= albinos) are very easily sunburned
23
SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.
Many reasons account for the manifestation of a recessive genetic disorder
within a human population
1. Prolonged geographic isolation and inbreeding

there is an increased probability that a recessive allele breaks through =
becomes dominant in an homozygous individual if close relatives marry and have
children

the manifestation of recessive disorders can frequently be observed in small
societies which were geographically isolated for extended periods of times,
e.g. those living on an island, or in a hard-to-reach valley, and in small
populations which showed higher incidences of consanguinity (= first cousin
marriages)
- a classical example is hereditary deafness which runs amongst certain
families on Martha’s Vineyard, a small island off the coast of Massachusetts
- e.g. the inheritance of pyruvatekinase deficient hemolytic anemia, an
autosomal recessive disorder which runs in certain Amish families in
Pennsylvania
2. Co-evolutionary aspects & Adaptive reasons

the allele for sickle cell anemia manifested itself in a high percentage within the
African American population since it gives its carriers a certain
advantage/protection against malaria infection

carriers of the sickle cell anemia allele in Africa are less likely affected by
malaria-causing Plasmodium strains
IIII..
D
Doom
miinnaanntt ddiissoorrddeerrss

are serious disorders caused by a dominant allele
 e.g. extra or webbed fingers or toes are inherited in a
dominant way

Examples of dominant disorders in humans are:
11.. A
Acchhoonnddrrooppllaassiiaa
- heterozygote individuals with the defect allele have shortened arms
and legs
- the homozygous dominant genotype leads to death of the embryo
already before birth
- 99.99% of the human population is homozygous
for the ‘normal’, recessive allele
22.. H
Heerreeddiittaarryy rreettiinnoobbllaassttoom
maa
- hereditary retinoblastoma (Rb) is inherited as an autosomal
dominant trait
- a retinoblastom is a tumor of the undifferentiated retina in infants;
children carrying the allele for Rb develop eye tumors early during
infancy
24
SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.
-
-
it is caused by point mutations or deletions of the Retinoblastoma
(RB-1) gene, which is located on chromosome #13 (13q14.2)
the RB gene which codes for the cell cycle-regulating protein pRb
due to the dominant character of the Rb allele, it “runs in families”;
every generation shows family members being affected by the
disorder, i.e. being diagnosed with retinoblastoma
since it is an autosomal disorder it affects males and females
equally (see family pedigree for the “Rb trait” below)
Pedigree of a family with the Rb allele
(Typical family pedigree of an autosomal dominant disorder)
Alleles
X
(Genotype)
female
cell
male
cell
Family Pedigree
Generation
Parents
P
F1
F2
Cancer
Healthy
33.. A
Allzzhheeiim
meerr’’ss ddiisseeaassee
- disease of former US president Ronald Reagan
- leads to mental deterioration due to amyloid protein plaque
formation in the limbic system of the brain
- the onset of this neuro-degenerative disorder is usually very late in
life
- the cause and the incidence is not known

As we clearly learn from these devastating dominant inherited disorders,
dominant in the genetic sense, does not imply that a dominant allele is somehow
better than the corresponding recessive allele nor does it mean that a dominant
allele is more frequent in a population
“Dominant … recessive tells only about the destiny of the allele and its
genes within the cells of an organism…”
25
SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.

Lethal dominant alleles are much less common than lethal recessive alleles
 this is explained by the fact that a lethal dominant allele cannot be
carried by a heterozygous individual for a long time and usually not
long enough to reach the reproductive age
 while on the other hand, a lethal recessive allele can be carried by
many heterozygous members of a population without affecting
themselves in a serious way

usually the patterns of inheritance are more complex than the mono- or
dihybrid crosses described by Mendel with the common garden pea; it is
therefore not surprising that one observes many variations to Mendel’s
patterns of inheritance, especially when one studies heritable traits in complex,
multicellular organisms, such as animals and humans

there are many patterns observable in nature where, e.g. one allele is not
completely dominant to the other allele, or where more than one gene is
responsible for the expression of a certain phenotype; the following sections
below will look up some of these variations to Mendelian genetics in more detail
R
Ruullee ooff IInnccoom
mpplleettee D
Doom
miinnaannccee

when Mendel crossed his true-bred and parental yellow-seed plants with greenseed plants, he always received yellow-seed pea plants; he observed complete
dominance

however, there are many examples known in nature, where crossing of two
different pure-bred varieties leads to offspring which show a blending of a the
inbred phenotype; geneticist speak then of an incomplete dominance; in this
case neither of the two inherited alleles is dominant
Examples of incomplete dominance in nature
1. Hair form in mice
 Crossing of straight- and curly haired mice always
produces mice with wavy hairs
2. Color and petal form of orchids
 Crossing of red orchids with straight petals with white orchids with curly petals
results in pink orchids with wavy petals
3. Petal color of snap-dragons
RR
 crossing of homozygous parental red (R
R) and white ( ) snap dragons leads
to heterozygous ppiinnkk ppllaannttss in F1generation (see Graphic below)
 the F1-offspring have an appearance in between the phenotypes of the two
parent varieties
 both parental phenotypes (red and white blossom) reappear again in the F2
generation after crossing two heterozygous F1 offspring (Rr x Rr)
 in agreement with Mendel’s law , ¼ of the F2 offspring have red blossoms and
¼ is white colored, while 2/4 of the F2 offspring are pink-colored
26
SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.
Incomplete dominance in snap dragon plants
• e.g. Heritable trait = petal color of snapdragon plants
Phenotype
X
P
RR
Genotype
rr
F1
X
R
Rr
Sperm
F2
R
R
RR
Rr
r
Rr
rr
r
Eggs
Punnett Square
Genotypes
F2
25%
50%
25%
Phenotypes
Graphics©E.Schmid/2002
27
SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.
“Since the original traits reappear in the F2 generations of incomplete
inherited characteristics, incomplete inheritance is NOT a violation of
Mendel’s laws … incomplete dominance with its mixed phenotypes does
not validate the historical Lamarckian blending hypothesis …”
4. Familial Hypercholesterolemia (FH) in humans
- FH is a cholesterol level disorder in humans which involves a recessive h
allele; the “h” allele is responsible for the onset of the typical health
complications of FH
- Human homozygous regarding the defective “h” allele (= hh genotype) have
enormously high blood cholesterol levels (> 800mg/dl Cholesterol) which
leads to a serious of health complications in the affected human individuals
including atherosclerosis, cardiovascular problems, heart attacks and stroke
in young age, commonly before the age of 40
- Humans with the HH genotype have normal cholesterol levels (, 200mg/dl),
while heterozygote persons (Hh) also have elevated cholesterol levels (about
twice as normal) ( see Graphic below)
 ergo: the h allele is not completely recessive, but leads to a “mixed
phenotype”, which is expressed as an intermediate elevated cholesterol
level (around 500mg/dl) in heterozygous human individuals
 incomplete dominance of the H allele over the h allele
-
-
-
the H allele is located on human chromosome # 19; it is comprised of a gene
that codes for the LDL receptor (= LDLR)
the LDL receptor is a cell surface-exposed receptor protein that binds to the
ApoB protein of LDLs (= Low Density Lipoproteins) and helps to clear these
cholesterol-containing lipid particles from the blood stream
heterozygotes (hH) have only half the number of LDL receptors on their (liver)
cells, while homozygous hypercholesteremic individuals do not show any LDL
receptors on their cells
the defective h allele in humans suffering from FH usually carries one or more
mutations in the LDLR gene (see Figure below)
28
SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.
Familiar Hypercholesterolemia (FH):
an example of incomplete dominance in Homo sapiens
Clinical manifestations/symptoms:
 High LDL and cholesterol levels in blood plasma
 Early arteriosclerosis (usually before age 40)
 Xanthomas in skin and tendons
 Reduced life expectancy
1000
800
Cholesterol
(mg/dl)
Phenotype
= Plasma Cholesterol
Concentration
600
400
200
0
FH
Homozygous
FH
Heterozygous
Normal
Genotype
-/-
-/+
+/+
29
SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.
Molecular genetics of Familial Hypercholesterolemia (FH)
 point mutations (dots) and deletions (red lines) of the human LDL receptor protein
prevents intracellular uptake of LDL-bound cholesterol via ApoB protein
0
1
10
2 3 4 5 6
kb
20
30
40
45
7 8 9 101112 1314 15 1617
18
Exons
5’
Chr. #19
3’
12bp
8 kb
7.8 kb
4
kb
mRNA signal sequence
5.5 kb
LDL-Receptor5’
mRNA
0
LDL
Point mutation
3’
1.0
2.0
3.0 kb
Functional Domains
LDL binding
Apo
B-100
Growth
Carbohydrate
LDL-Receptor
Membrane spanning
Cytoplasmic
Normal
CTGGTGCAA
Valine408
no intracellular
LDL transport !
Mutated
CTGGTACAA
Methionine408
30
SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.
E
Exxaam
mpplleess ooff iinnhheerriittaannccee ppaatttteerrnnss w
wiitthh m
moorree tthhaann 22 aalllleelleess ppeerr ggeennee ((ccoo-ddoom
i
n
a
n
c
e
)
minance)

there are cases where there are more than two alleles responsible for one
characteristic and in some cases the genotype does not always dictate the
phenotype in a classical Mendelian pattern

one classical example for this kind of inheritance pattern in humans is the ABO
blood type, which has been first described by Karl Landsteiner in 1900

Knowledge of an individuals blood type is extremely important in transfusion
therapy to save a persons life after massive loss of blood due to, e.g. a serious
car accident or other traumatic body injuries
- the blood of donor and patient must be compatible, otherwise, a serious
adverse immunological reaction would be triggered in the patient’s body, a
reaction which could lead to the death of the transfusion-receiving patient
- The adverse immunological reaction (which involves the massive production
of antibodies) results in the clumping (or “agglutination”) of red blood cells
(erythrocytes) in the patient’s body leading to clotting within the blood vessels,
malnutrition of the body’s cells and the final failure of affected tissues and
organs
 antibodies are complex proteins produced by the B-lymphocytes after
encounter of the body with foreign structures, such as proteins, bacteria
and viruses
 antibodies are very specific and only bind to their corresponding structures,
their so-called antigens
 in the case of the ABO blood type, the immune response-triggering antigen
is located on the surface of red blood cells (see Graphic below)
1. the ABO blood group system in humans

there are three alleles (IA, IB and i) which lead to six different genotypes (IAIA, IAi,
IBIB, IBi, IAIB and ii)

the IA, IB alleles are dominant to the i allele, which means that both genotypes
IAIA and IAi express blood type A; the recessive homozygotes ii have blood type
O

IA and IB exhibit co-dominance, which means that both alleles are expressed in
heterozygous individuals
31
SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.
The three alleles of the human blood type
Allele
IA
For simplicity we call
these:
A
IB
B
i
O

these ssiixx ggeennoottyyppeess lead to ffoouurr pphheennoottyyppeess or so-called ABO blood groups
(A, B, AB and O)

each of us has two ABO blood type alleles, because we inherit one blood type
allele from our biological mother, and one Allele from our biological father

in the case of the genotype AB, the information of both Alleles is expressed in
the phenotype
 A and B are co-dominant

the letters for the phenotype refer to two carbohydrate molecules designated A
and B which are exposed on the surface of red blood cells (= erythrocytes)
The A, B, and O alleles and the human ABO blood types
Parent
(haploid gametes)

Offspring
(diploid)
Allele
((M
Mootthheerr))
Allele
((FFaatthheerr))
G
Geennoottyyppee
P
Phheennoottyyppee = B
Blloooodd
ttyyppee
A
A
AA
A
A
B
AB
AB
A
O
AO
A
B
A
AB
AB
B
B
BB
B
B
O
BO
B
O
O
OO
O
a person with blood group A or B has erythrocytes coated with either
carbohydrate A or B; a person with blood type AB exposes both carbohydrates (
A and B) on the surface of its red blood cells (see Graphic below)
 a person with O-type blood doesn’t expose any of these two sugars
32
SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.

the ABO blood type plays an important role in the successful transfusion of
donated blood into a patient
- donating blood can be life saving for people who suffer from massive blood
loss due to accidents or caused by severe blood diseases

the donor blood has to be compatible (= matching) with the patients blood
group, otherwise the donor blood cells will be recognized as foreign by the
antibodies of the patient’s immune system
ABO blood types, antibodies & blood transfusion medicine
The blood of the human body does not store antibodies for antigens (Ags) it has
never encountered. The ABO blood system, however, is an interesting exception to
this immunological rule. In this system, antibodies to other blood types occur
naturally whenever the RBC antigen (A or B) is not present. An individual with blood
type A possesses the type A antigen on his/her red blood cell surface and the anti-B
Ag antibody; the type B individual has the type B antigen on his/her red blood cell
surface and carries anti-A antibodies; RBCs of type O blood contain neither the A
nor the B antigens on their surface, but type O blood contains both, anti-A and anti-B
antibodies; RBCs of type AB blood contain both, the A- and the B-antigen on their
surface, but no antibodies against A or B are found in type AB blood.
This knowledge translated into blood transfusion medicine would mean, that if a
blood type A person mistakenly would receive type B blood from a donor, the Bantigens on the surface of the donor’s RBCs would be agglutinated by the existing
anti-B antibodies present in the type A blood and the vicious cycle would start in the
recipient’s body.

to avoid a massive, fatal immune response within the patient’s body after blood
transfusion, the blood type of the donor has to be determined and matched with
the patient’s blood type
General rules in blood transfusion medicine
1. Never allow an individual to receive an antigen that does not occur in his
or her blood
2. Since type O blood contains neither the A antigen nor the B antigen it
does not trigger an immune response in either blood type; it therefore
considered to be the “universal donor” blood type and may be transfused
to any blood type
3. Since type AB blood contains both, antigen A and antigen B, but no
antibodies to the A- or B antigen, an individual with blood type AB can
receive blood from any of the blood types; blood type AB is therefore
known as the “universal recipient”
33
SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.
The ABO phenotype: The Antigens on the surface of red blood cells (RBCs)
alleles
IA
i
IB
gene expression
Chromosome
#9
(9q34.1)
no enzyme
“A”
“B” enzyme
Sugar residues
Pr
“H” enzyme  all humans have it!
“A” enzyme
“B” enzyme
Pr
“A”
antigen
A
Pr
“B”
antigen
“A” + “B”
antigen
B
AB
Blood type
“O”
antigen
O
Graphics©E.Schmid/2002
34
SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.

a person’s ABO blood group can be experimentally determined by performing a
so-called agglutination test
- due to the existence of many blood-borne diseases, such as HIV, hepatitis B
and C, herpes virus, etc., the necessary experimental steps of a blood typing
test have to be performed in a specially equipped laboratory to avoid
contamination of the test-conducting personnel
- for safety reasons, most community and 4-year colleges won’t allow these
tests preformed by students during the biology education
- before the introduction of more accurate molecular biological testing methods,
such as PCR, blood tests were frequently used also in so-called paternity law
suits to confirm the identity of the biological father of a child

An individuals blood type is experimentally determined by mixing a drop of the
blood with serum containing high titers of antibodies to the A antigen (= Anti-A
serum) and by mixing a drop of their blood with serum containing antibodies
against the B antigen (= Anti-B serum); blood samples and sera are gently mixed
in special depression slides and the samples are observed for the occurrence of
agglutination in the wells;
- if a person’s blood shows agglutination of her/his RBCs in the presence of
Anti-A but not of Anti-B serum, then the person’s blood type is A, and vice
versa
- if the blood in both wells of the depression slide agglutinates in the presence
of Anti-A and Anti-B, the person’s blood type is AB
- if no agglutination takes place at all, the tested person’s blood has blood type
O
P
Plleeiioottrrooppyy

pleiotropy is another exception to Mendel’s classical laws of inheritance; under
pleiotropy geneticists mean, that one allele/gene influences many characteristics;
one genotype  many phenotyes

pleiotropy is observed in the human autosomal disorder sickle cell anemia

in sickle cell anemia, the defect of one single allele (which leads to an abnormal
hemoglobin molecule in homozygous individuals) affects the body in multiple
ways, i.e. clumping of red blood cells, clogging of small blood vessels, heart
failure, pain & fever, etc.
 only homozygous individual usually suffer from the disease

but since the sickle cell and non-sickle cell alleles are co-dominant, heterozygous
carriers can suffer from complications under certain conditions (e.g. low oxygen
pressure, high elevations)
 1 out of 10 African Americans are carrier of the sickle cell allele!
35
SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.
P
Poollyyggeenniicc iinnhheerriittaannccee ppaatttteerrnnss

if many genes influence and contribute to the expression of one single
characteristic, geneticists speak of polygenic inheritance

many characteristics of humans vary within a population along a continuum
rather than by one sharp, defined phenotype
examples of polygenic inheritance patterns in humans are certain body features,
such as skin color, hair color or body height


all of these body features rather follow a continuum and are the result of the
additive contribution of two or more genes on one distinct phenotype

e.g. in a hypothetical model lets say a ‘dark skin’ allele is responsible for a
strong pigmentation and consists of 3 genes called A,B,C
 each gene contributes ‘one unit of darkness’ and is
incompletely dominant to the three corresponding genes
aa,,bb,,cc of the ‘‘lliigghhtt sskkiinn’’ aalllleellee

the genotype of the homozygous ‘dark skin model’ phenotype would be
AABBCC, while the genotype of the homozygous ‘light skin model’ would be
aaaabbbbcccc

AaaB
crossing of both would lead to a heterozygous genotype (A
BbbC
Ccc) in the F1
generation which would have light-brown skin color

after crossing of both heterozygous F1 ‘light brown model’ offspring we would
expect 64 different genotypes and 7 different ‘skin color’ phenotypes in the F2
generation
( see Punnett square!)
 since there are probably more than only three genes
responsible for our skin type, we would indeed expect a
continuum expression of our skin color within the human
population
LLiinnkkeedd ggeenneess

geneticists observed in crossing experiments with plants and certain flies, that
alleles/genes which are coding for different traits but which are located on the
same chromosome tend to be inherited together (= linked genes); a dihybrid
croos performed with these traits would NOT receive the classical Mendelian
9:3:3:1 inheritance pattern regarding the phenotypes

linked genes are genes whose loci are on the same chromosome and usually
close together
36
SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.

they are therefore often inherited together and don’t exactly follow the Mendelian
law of independent assortment of genes

the first evidence of linked genes was reported in 1908 by W. Bateson & R.
Punnett (the inventor of the Punnett square) when they did crossing experiments
with doubly heterozygous sweet pea plants (see Graphic below)

they studied two characteristics:
Allele

1. flower color:
dominant Purple
recessive Red
P
p
2. polen shape:
dominant Long
recessive short
L
l
after crossing two heterozygous F1 offspring
genotype
PpLl
genotype
x
PpLl
 they did not receive the predicted 9 : 3 : 3 : 1 ratio for the dihybrid cross in the F2
generation

the discrepancy in the phenotypic ratio could be explained by the fact that the
gene coding for the color (P= purple; r= red) and the gene coding for the polen
shape (L = long; l = round) were located on the same chromosome;

both genes were so-called linked genes; they were not independently assorted
during meiosis

the often observed “inbetween” new phenotypes in breeding experiments with
linked alleles and the discrepancy between the expected 3:1 inheritance pattern
for linked genes is majorily attributable to new allele combinations due to
crossing over events happening during meiosis in these organisms (see
Graphic below)
- the new phenotypes widely observed with linked alleles are not due to
independent assortment during meiosis but are recombinants generated
through crossing over events occuring during prophase I of meiosis I
- the lower the percentage of recominant phenotypes received after breeding
experiments involving linked alleles, the closer together the two alleles are
located on the same chromosome
37
SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.
Inheritance patterns of linked genes/alleles
• Bateson/Punnett experiments with sweet pea plants (1908)
Phenotype
X
PpLl
PpLl
Phenotypes
Genotype
Predicted
Offspring
(9:3:3:1)
Purple-Long
Purple-Round
Red-Long
Red-Round
Observed
Offspring
215
71
71
24
284
21
21
55
recombinants
Interpretation: Genes/alleles are on the same chromosome –
Geneticists say alleles are linked
P L
F1
P generation
p l
Sperm
p
l
P L
Meiosis
Oocytes
p
p l
P L
l
P L
Expected
Phenotypes
3 Purple-Long
1 Red-Round
38
SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.
S
Seexx--LLiinnkkeedd IInnhheerriittaannccee

in sexually reproducing organisms, not all genes or alleles coding for heritable
traits are located on autosomes

the genes for many traits are found located on the so-called sex- or gender
chromosomes

many traits have been found to be located only on the (in humans) much larger X
chromosome but not on the relatively small Y chromosome (see Figure below);
this is why these traits are inherited in a unique, so-called X-linked fashion which
is different to traits located on autosomes

in humans, the genes for many heritable disorders, such as SCID, muscular
dystrophy, hemophilia and red-green color blindness, are located on the Xchromosome and are not found and the Y-chromosome; they are therefore
inherited in a X-linked manner (see Figure below)
Location of genes located on the X-chromosome
( mutations of these genes are responsible for X-linked inherited disorders)
22
Duchenne muscle dystrophy
2
(Xp21)
21
p
Retinitis pigmentosa-2
1
11
1
11
12
13
Spino-bulb. Muscle atrophy
(Type: Kennedy)
(SBMA gene; Xq21.3-22)
X-chromosome
(Metaphase)
21
Hereditary nephritis
q
2
22
Fragile X-syndrome
23
24
25
26
(FMR1 gene; Xq27.3)
Hemophilia A
(CF VIII gene; Xq28)
27
28
Red-green color blindness
(Rhodopsin gene)
39
SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.

the study of inheritance of genes located on sex chromosomes was pioneered
by the great American geneticist T. H. Morgan and his students at the beginning
of the 20th century

even though Morgan studied fruit flies (Drosophila), we know today, that the
same genetic principles of sex-linked or X-linked inheritance apply to humans
as well

since males and females of higher biological organisms differ in their sex
chromosomes, inheritance patterns for X-chromosome linked genes (alleles) vary
between the sexes and affect the human gender differently (see Figure below)
S
Seexx--lliinnkkeedd iinnhheerriittaannccee iinn D
Drroossoopphhiillaa

in the fruit fly Drosophila, the alleles for eye color and for body color are on the X
chromosome, but not on the Y chromosome

W ) is dominant inherited, the white eye color (w
w ) is
the red eye color allele (W
the recessive allele
 the tan body color (y+) is dominant over the yellow body color (y)
 geneticists say, that red eyes are dominant, X-linked, while white
eyes are X-linked, recessive inherited
40
SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.
Autosomes, sex chromosomes & X-linked alleles
22 pairs of homologous chromosomes in humans
1
11
2
12
3
13
4
14
15
5
6
16
17
7
18
8
19
9
20 21
10
22
Autosomes
Male
Female
or
X Y
X X
Sex or gender chromosomes
X-linked genes
Male-making genes
Homologous sections
X
Y
Chromosome
©ESchmid/MesaCollege2001
41
SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.
P
Phheennoottyyppee aanndd ggeennoottyyppee ooff tthhee sseexx--lliinnkkeedd ttrraaiitt ““eeyyee ccoolloorr”” iinn D
Drroossoopphhiillaa
P
Paarreennttss
((== P
P ggeenneerraattiioonn))
Phenotype
Genotype
Gender chromosome

the female parent is homozygous; the red-eyed male parent is hemizygous
O
Offffsspprriinngg
((FF11 ggeenneerraattiioonn))
Genotypes
Phenotypes

all female offspring are rreedd--eeyyeedd heterozygous; all male offspring are w
whhiittee--eeyyeedd and
hemizygous
42
SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.
X
X--lliinnkkeedd iinnhheerriittaannccee iinn hhuum
maannss

certain traits and (unfortunately many) disorders in humans are also inherited in a Xlinked manner, such as:
1. Hemophilia
- the X-linked inherited disorder hemophilia is due to a mutation of a gene coding for a
blood coagulation factor; the gene is located on the long distal arm of the Xchromosome (see Figure below)
Molecular biology of hemophila
many point mutations have been observed in the Taq1 recognition sequence TCGA of
the gene coding for human coagulation factor VIII; deamination of DNA to TTGA leads
to a stop codon (TGA) and to shortened mRNA versions of the VIII gene;
that mutation leads to a Bcl I recognition site in exon 17-18 which is routinely used for
clinical diagnostic of the disorder by applying a method called RFLP-analysis
Normal gene:
1165 bp DNA fragment
Hemophilia gene:
879 bp DNA fragment
Hemophilia & Mutation of the human gene for coagulation factor VIII
Activated Blood
Coagulation Factor VIII
50kDa
A1
A2
43kDa
Ca2+
A3
C1 C2
73kDa
Thrombin (IIa)
Factor VIII Precursor
1
NH2
2332aa
A1
Factor VIII Gene
A2
B
A3 C1 C2
Exon 17 + 18
1
COOH
186,000bp
5’
X-chromosome
(Xq28)
-
3’
26 exons
Mutated region
the mutated coagulation factor protein is defect and not able to successfully
contribute to blood clot formation after a wound appeared, e.g. after trauma or injury
as a consequence, the affected hemophilic individual is permanently bleeding
therefore hemophilic persons are often referred to as “bleeders”
hemophilia affected many male family members of the former British Queen Victoria
(see Figure of Queen Victoria’s family pedigree below)
43
SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.
Family pedigree for the X-linked inherited disorder hemophilia
(Classical example of an X-linked inheritance pattern)
Queen Victoria
of England
Prince Albert von
Sachsen-Coburg-Gotha
carrier
Prinz Heinrich
v. Battenberg
Alice
Heinrich
v. Preussen
Irene
Ludwig v. Hessen
Alexandra
Frederick
Waldemar
Heinrich
Leopold
Beatrice
Duke of Albany
CzarNikolaus II
Alexis
Alice
Ruprecht
Alfonso
of Spain
Gonzalo
2. Red-green color blindness
- red-green color blindness is another heritable human trait which is inherited in
an X-linked fashion
- the alleles responsible for red and green color vision of humans, both, are
located on the X-chromosome
- the allele which causes red-green color blindness is recessively inherited
- a human female who is homozygous for the recessive red-green color blindness
allele and a hemizygous male are not able to discriminate between the red and
green color
- the disorder is most likely caused by unequal recombination events between two
X-chromosomes during meiosis leading to dys-functional, shortened versions of
the “green color vision allele” or to a completely missing green color vision allele
in the X-chromosome (see Figure below)
44
SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.
Molecular genetics of red-green color blindness, an X-linked inherited human
disorder
Normal organization of the rhodopsin genes for red and green color vision on the X-
X
X-chromosome
or
X
or
X
“red color vision allele”
“green color vision allele”
Different red-green color vision mutations in humans
due to unequal crossing over between two X chromosomes
X1
X2
Genomic
crossing over
Phenotype
(= clinical picture)
X
Green blindness (2%)
X
Normal color vision
X
Red blindness (? %)
X
Red- Green blindness
(1%)
X
Red- Green blindness
X
Red blindness (? %)
deletions
Graphics©E.Schmid/SWC2002
45
SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.
3. SCID (Severe combined immunodeficiency)
- SCID is a human disorder which is inherited in a X-linked fashion
- The disorder, often referred to as “bubble-boy syndrome”, is characterized by a
severely impaired immune system of the affected individuals
- The affected humans have a short life expectancy due to high vulnerability to
microbial infections
- Children diagnosed with SCID have functional defects in specialized white blood
cells, the so-called B- and T-lymphocytes
- The disorder is caused by mutations of genes coding for essential components of
the signal transduction cascade of lymphocytes
- frequently observed mutations in SCID patients are found in the genes for the
Interleukin 2 receptor gamma (IL2Rγ), a gene which is located on the Xchromosome

as the example for the X-linked inherited disorder hemophilia shows below, X-linked
inherited disorders affect mostly males
Results of a mating between a normal (non-carrier)
female and a hemophilic male

all of the daughters of this couple inherit an X chromosome with the mutation from their
father, and will be carriers; all the sons inherit a normal X chromosome from their
mother.
46
SAN DIEGO MESA COLLEGE
SCHOOL OF NATURAL SCIENCES
Introduction to Molecular & Cell Biology (BIO 200); Instructor: Elmar Schmid, Ph.D.
Diagnosis of human genetic disorders

Many genetic disorders can be detected before birth by fetal testing with the help of
different clinical procedures and techniques, such as
11.. A
Am
mnniioocceenntteessiiss
 is done between the 14th and 16th week of pregnancy
 a sample (2mL) of the amniotic fluid is withdrawn in a hospital and
biochemical tests as well as karyotyping is performed
 the complication rate is about 1-2%
22.. C
Chhoorriioonniicc vviilllluuss ssaam
mpplliinngg ((C
CV
VS
S))
th
 performed between the 8 and 10th week of pregnancy
 a small amount of embryonic tissue, the so-called chorionic villi, are taken
from the placenta for testing
 this procedure is faster due to the rapid growth of the embryonic cells of
the villi
33.. U
Ullttrraassoouunndd iim
maaggiinngg
 sonic sound waves are used to check for eventual anatomical
deformations or simply to examine the position of the fetus

all three medical methods are usually reserved for situations in which the possibility of
genetic disorders is significantly increased such as in
 35 year old or older women with their first pregnancy
 couples with a family history for a certain hereditary disorder
47