Download beyond Mendel - the molecular basis of inheritance

beyond Mendel - the chromosomal
basis of inheritance
biology 1
• Mendel’s Laws based on chromosomal
behavior
• Specific advances in the knowledge of
genetics
– Sex-linkage
– Recombination
– Linked genes
– Sex-linked disorders
– Alterations of chromosome
number/structure
A chromosome basis for Mendel
• Observed by late 1900s;
– Chromosomes and genes are both paired in diploid
cells
– Homologous chromosomes separate and allele pairs
segregate during meiosis
– Fertilization restores the paired condition for both
chromosomes and genes
• This led to the chromosome theory of inheritance
– Mendelian factors or genes are located in
chromosomes
– It is the chromosomes that segregate and
independently assort
• Thomas Morgan substantiated this theory
with work on fruit flies, Drosophila (2n = 8)
• Adopted a new method of symbolizing
genes and alleles
– A gene’s symbol is based on the first mutant,
non-wild type discovered (e.g. w = white eye
allele in Drosophila)
– If the mutant is dominant, the first letter is
capitalized (e.g. Cy = curly wings in Drosophila)
– Wild type (normal) gets superscript + (e.g. Cy+
is the allele for normal, straight wings)
Sex-linkage
• Morgan crossed a white-eyed male (w) with a red-eyed
female (w+w+)
– In the F1, all progeny had red eyes, implying that red-eye was
dominant
– In the F2, white-eye trait was only found in males - females were
always red-eye
• Deduction: the gene for eye color is on the X chromosome,
since
– If eye color is located only on the x-chromosome, then females carry
to copies of the gene (XX), while males (XY) only carry one
– Since the mutant allele is recessive, wa white eyed female must
have that allele on both X chromosomes, which would be impossible
for F2 females
– A white-eyed male has no wild type to mask the recessive mutant
allele, so a single copy of the mutant allele confers white eyes
Linked genes
• Linked genes are located in the same
chromosome and tend to be inherited
together (ie, do not sort independently,
9:3:3:1 ratio is not preserved)
– For example, in a non-linked dihybrid testcross, e.g.
YyRr
x
yyrr
Yellow round
F1
YyRr
Yellow round
1
yyrr
green wrinkled
:
1
:
(Parental types)
Green wrinkled
yyRr
green round
1
Yyrr
yellow wrinkled
:
1
(Recombinant types)
• If genes are totally linked, some possible phenotypes
should not appear (although sometimes they can, if linakge
is not complete)
• For example, Morgan crossed black body (b), normal wings
(vg+) vs. wild type body (b+), vestigial wings (vg)
Phenotypes
Body/wing
genotypes
results if
unlinked
results if
linked
actual results
Black, normal
bb vg+ vg
575
-
206
Gray, normal
Black, vestigial
b+b vg+vg
bb vgvg
575
575
1150
1150
965
944
Gray, vestigial
b+b vgvg
575
-
185
Recombination frequency = 391 recomb./2300 offspring = 17%
• Conclusion: the two genes are neither completely linked or
unlinked
• If genes are completely linked, then expect only parental types in offspring
• Crossing over in Prophase I accounts for recombination of linked genes
• Genes that are located in the same chromosome close to each other are
less likely to separate during synapsis. Genes that are further apart are
more likely to be separated
• If crossing-over occurs randomly, percentage of crossing-over can be used
to map location of genes on a chromosome
Loci
Recombination frequency
Approximate Map Units
(centimorgans)
b vg
17.0%
18.5 (9 + 9.5 = 17)
cn b
9.0%
9.0
cn vg
9.5%
9.5
17
9.0
b
9.5
cn
vg
• When linked genes are further apart than 50 cM, they are indistinguishable
to non-linked genes
• Cytological mapping can now pinpoint precise location on chromosome
Sex-linked disorders
• Since the x-chromosome is larger, there are more x-linked
traits: most have no homologous loci on the y-chromosome
• Most genes on the y-chromosome have no x-counterparts, and
encode traits only found in males
• Examples of sex-linked traits include color blindness and
hemophilia.
– Fathers pass X-linked alleles to only, and all of their daughters.
Fathers cannot pass x-sex-linked traits to sons
– Mothers can pass X-linked alleles to both sons and daughters
– X-sex-linked traits are rarer in females since they tend to be
recessive, and thus require a homozygous condition
– Any male that receives an X-sex-linked chromosome, recessive or
not, will express it, since they are hemizygous
– As a consequence, males tend to display more sex-linked
disorders.
X-inactivation
• To prevent females from receiving a double-dose of
sex-linked traits, one X-chromosome is typically
inactivated, contracting into a dense object called a
barr body
• Barr bodies are reactivated in gonadal cells for meiosis
• Choice of which X to inactivate (maternal or paternal
inherited) is randomly selected in embryonic cells
• Thus heterozygous females display sex-linked traits on
a 50/50 basis (e.g., calico cats)
• Formation of barr body appears to be by methylation of
cytosine
Alteration of chromosome number
• Meiotic nondisjunction: a homologous pair
does not separate in Metaphase I, or
chromatids do not separate in Metaphase II
• Mitotic nondisjunction: occurs at metaphase.
If early in embryonic development, can be
passed onto a large number of cells
• Aneuploidy - an abnormal number of
chromosomes (trisomic or monosomic); for
example, Down syndrome is trisomy of
chromosome 21
• Polyploidy - a chromosome number that is
more than two complete chromosome sets;
this is very common in plants
Alteration of chromosome structure
• Fragments breaking off from chromosomes may
result in deletions
• Addition of those fragments to:
– Homologous chromosomes causes a replication
– Nonhomologous chromosomes causes a translocation
– Original chromosome in reverse order causes an
inversion
• Crossovers are usually reciprocal, but sometimes
a chromatid gives up more genes than it receives
in an unequal crossover (creates one deletion and
one duplication)
Human disorders resulting from
chromosomal alteration
• Down syndrome effects 1/700. The result
of trisomy on chromosome 21 (an
autosome), causes specific facial
features, heart defects, retardation, and
proneness to leukemia
• Sex chromosome aneuploidies are
typically less severe because
– The Y chromosome carries less genes
– Copies of the X-chromosome may be
inactivated as barr bodies