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Human Genetics
NonAutosomal Inheritance
NonAutosomal Inheritance
X-Linked Dominant
X-linked Recessive
Y-linked
Mitochondial
The Sex Chromosomes
The Sex Chromosomes
There is no universal system; can be either
genetic or environmental
Humans and fruit flies have the XY genetic
system
Y chromosome
“single-issue” chromosome designed to
determine sex
X chromosome – ‘controlling’
For males, it’s the curse of the ‘lone X’
Females also prone to certain conditions
The Sex Chromosomes
XX:XY (males heterogametic)
ZZ:ZW (females
heterogametic)
Variations include X1X2Y or
XY1Y2
Sex-specific chromosomes
tend to be small and genepoor overall, but enriched for
genes specifically benefiting
the sex that harbours them.
In any given species, cytogenetic pattern between
homologous chromosomes is similar
In most species, sex chromosomes tend to be
heteromorphic (variations in shape, size and gene
content)
Gene clustering patterns are also different
Y Chromosome
‘hall of mirrors’ – full of
palindromes
50Mb size - ~50 genes
2 domains
Pseudoautosomal region
(PAR) – 5%
Non-recombining regions
(NRY) – 95%
HMG3 pages 367-372
Active genes on the human Y chromosome
Yellow bar, euchromatic NRY (nonrecombining region);
black bar, heterochromatic portion of
NRY;
red bars, pseudoautosomal regions
Genes to right: active X-chromosome
homologues.
Genes to left: lack known X
homologues.
Genes in red: widely expressed
housekeeping genes;
genes in black: expressed only in
testis
genes in green are expressed neither
widely, nor testis specifically
AMELY (amelogenin Y) is expressed
in developing tooth buds,
PCDHY (protocadherin Y) is
expressed in the brain)
Y chromosome shows the accumulation of spermatogenesis
genes and an overall functional decay typical of male-specific
chromosomes.
Active genes on NRY region classed into 3 types on the basis
of tissue expression and homology to the X
Class 1: housekeeping genes with ancient homology to X
Class 2: testis-specific genes.
Class 3: genes variously similar to both classes 1 and 2,
as well as other genes that might be decaying towards
pseudogene status, or the persistence of which might reflect
additional evolutionary factors at work on the Y chromosome.
Genes that belong to classes 1 and 2 seem to underlie the
medical disorders Turner syndrome and male infertility,
respectively.
Y Chromosome Genes
Y-chromosome Inheritance is
Paternal
Pedigree of family with Focal
Glomerular Sclerosis
Is this trait Y-linked? Not necessarily- other pedigrees indicate it is
autosomal. Could also reflect a family exposure only seen in
males- this illness is associated with heroin abuse.
Principles of Medical Genetics 1998 Gelehrter et al. Lippincott Williams & Wilkins
Sex and Inheritance
Women have 2 X and men have and XY
 Homozygosity is possible for an X linked
gene
 Males with one X chromosome are called
Hemizygous
 Y chromosomes are also hemizygous.
 Genes on other chromosomes are affected
by whether an individual is a male or female
• Sex influenced
• Sex limited
Sex Makes Genetics More
Complex
Sex-limited traits- characteristic only appears
(or develops) in one of the sexes.
 Example: Ovary development in females; Sperm
development in males
Sex Influenced Trait- A sex-limited or sexinfluenced trait could be encoded by a sexlinked gene, but doesn't have to be. A sexlimited or sex-influenced gene could be located
on an autosome.
Cryptorchidism
(undescended testicles)
 Cryptorchidism is a genetic condition in which one or
both testicles fail to descend, and remain in the
abdomen. In development, testicles and ovaries develop
from the same embryonic tissue, located low in the
abdomen, roughly the same position ovaries are located
in fully developed females. Late in development, testicles
move from their abdominal position, through the inguinal
canal into the scrotum, which is essentially a small skin
bag which hangs outside the body.
 These genes are autosomal; males and females each
carry two alleles. Temperature in the abdomen is too high
to develop viable sperm, so males are sterile and greater
cancer risk.
 Only males can possible exhibit the condition, because
only males show the normal condition for testicle
behavior and position.
Male Pattern Baldness
What have you learned about this trait?
Not as well characterized as textbooks imply.
Pattern Baldness often incorrectly
identified as X-linked
Males can inherit baldness from either parent,
but when a son gets it from his father, both
father and son are bald. No one notices,
because we expect sons to look like their
fathers.
If a son loses his hair and his father doesn’t,
that’s striking, and people concluded (correctly)
is that Junior inherited baldness from his
mother.
But, with X-linkage, sons always inherit traits
from their mothers and never from their fathers.
Sex Influenced: Pattern Baldness
This trait may be polygenic [OMIM 109200]
The locus with strongest evidence of linkage
was mapped to 3q26 (AGA1) with a
nonparametric linkage (NPL) score of 3.97 (P =
0.00055). The other 3 regions were in
chromosomes 11q22, 18q11, and 19p13.
Hillmer 2008)
Consider two alleles, “bald” and “non-bald.”
The behaviors of the products of these genes
are highly influenced by the hormones in the
individual, particularly by the hormones
testosterone.
Sex Influenced: Pattern Baldness
 In the presence of high levels of testosterone, the
baldness allele is dominant (males).
 In the presence of low levels of testosterone, this allele
is recessive (females).
 All humans have testosterone, but males have much
higher levels of this hormone than females do.
 Dominance only matters in the heterozygote, so heterozygous
males experience hair loss and heterozygous females don’t.
 Homozygous females may experience no more than a thinning
of their hair, although some may develop bald spots or have
receding hairlines.
 Females with polycystic ovaries show pattern baldness
 http://query.nytimes.com/gst/fullpage.html?res=9802e1
d91638f935a25752c1a9659c8b63&scp=2&sq=male%2
0pattern%20baldness&st=cse
X-Linked Dominant Genes
The key for determining if a dominant trait
is X-linked or autosomal is to look at the
offspring of the mating of an affected
male and a normal female.
If the affected male has an affected son,
then the disease is not X-linked. All of his
daughters must also be affected if the
disease is X-linked.
X-Linked Dominant Inheritance
Rules for X-Linked Dominance
 The trait is never passed from father to son.
 All daughters of an affected male and a normal female
are affected. All sons of an affected male and a normal
female are normal.
 Matings of affected females and normal males produce
1/2 the sons affected and 1/2 the daughters affected.
 Males are usually more severely affected than females.
The trait may be lethal in males.
 In the general population, females are more likely to be
affected than males, even if the disease is not lethal in
males.
X-linked Dominance with
Lethality
X-Linked Recessive Inheritance
Sex Linked Recessive Punnet
Squares Are Useful
http://www.emc.maricopa.edu/faculty/farabee/BIOBK/BioBookhumgen.html
Images from Purves et al., Life: The Science of Biology, 4th Edition, by
Sinauer Associates and WH Freeman
X-Linked Recessive Rules
 As with any X-linked trait, the disease is never
passed from father to son.
 Males are much more likely to be affected than
females. If affected males cannot reproduce,
only males will be affected.
 All affected males in a family are related
through their mothers.
 Trait or disease is typically passed from an
affected grandfather, through his carrier
daughters, to half of his grandsons.
Glucose 6 Phosphate
Dehydrogenase Deficiency
X-linked Recessive
Trait
What happened for
the Proband?
He must have
inherited the disease
from his mother,
whose father had the
disease.
Principles of Medical Genetics 1998 Gelehrter et al. Lippincott Williams & Wilkins
Question
 What is the probability
person II-5 has inherited
the trait from her
mother?
 What is the Probability
she passes the trait on to
her son?
 What is the probability
she passes the trait on to
her daughter?
Answer
 What is the probability
person II-5 has inherited
the trait from her
mother? 50%
 What is the Probability
she passes the trait on to
her son?
50% x 50% [25%]
 What is the probability
she passes the trait on to
her daughter?
50% x 50% [25%]
X-linked Traits are common in
men and rare in women
Red-Green color blindness: X-linked trait.
It is easy to explain the phenotype and it's
relatively common.
7% to 10% of men are carriers
Calculations predict 0.49% to 1% for women.
It's commonness is possibly attributable to it not
being a serious disability in most cases and an
possible advantage in some situations
Mitochondrial Diseases
In 1963, researchers discovered mitochondria
have their own DNA (mtDNA), different than the
nuclear DNA (nDNA) found in the cells'
nucleus.
Mitochondrial and metabolic medical conditions
include more than 40 different identified
diseases with different genetic features.
The common factor among these diseases is
that the mitochondria are unable to completely
burn food and oxygen in order to generate
energy.
09_01.jpg
Mitochondrial DNA
Multicopy (466-806 per cell)
16,569 bp length and 0.68mM diameter
Genes lack introns
Maternally inherited
Sequenced in 1981 (Nature,1981, 290:457-65)
Mutation rate ~1/33 generations
Heteroplasmy (original and mutated forms coexist)
More stable for forensic analysis
Mitochondrial Inheritance is
Maternal
Ovum, originating in the female, have about
100,000 copies of mitochondrial DNA.
Sperm, originating in the male, has fewer than
100 copies, and these are probably lost at
fertilization.
Virtually all of your mitochondria come from your
mother.
Affected fathers produce no affected offspring,
while the offspring of affected mothers are all
affected.
Mitochondria
make ATP
Mitochondrial Inheritance
Mitochondrial Eve
(MEERF) Mitochondrial Encephalomyopathy
with ragged-red muscle fibers
Note mother passes
trait to all children but
the son doesn’t pass
it at all and all the
daughters pass it on.
Also note the
variability in the
symptoms as well as
their severity
Principles of Medical Genetics 1998 Gelehrter et al. Lippincott Williams & Wilkins
X-Linked Trait
What chance person
III-6 can pass on the
trait to sons?
Daughters?
What chance person
III-4 inherited the
trait? What chance
Person III-3?