Genetic Variability
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Genetic Variability
A population is monomorphic
at a locus if there exists only
one allele at the locus.
A population is polymorphic at
a locus if two or more alleles
coexist in the population.
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Genetic Variability
At a polymorphic locus, if one allele has a
very high frequency (> 99%), then the
other alleles are unlikely to be observed,
unless the sample size is very large. Thus, a
locus is commonly defined as polymorphic
only if the frequency of its most common
allele is < 99%. This definition is arbitrary,
and other criteria may be found in the
literature.
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Influenced by
mating system
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Gene Diversity
(Mean Expected Heterozygosity)
Gene diversity at a locus (single-locus expected
heterozygosity) is defined as:
m
h  1  x
2
i
i 1
where xi = frequency of allele i and m = total number of
alleles at the locus.
h = the probability that two alleles chosen at
random from the population are different from
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each other.
Gene Diversity
(Mean Expected Heterozygosity)
The average of the h values over all the loci studied,
H, can be used as an estimate of the extent of genetic
variability within the population. That is,
1 n
H
 hi
ni 1
where hi is the gene diversity at locus i, and n is the
number of loci.
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Gene Diversity
(Mean Expected Heterozygosity)
•H does not depend on an arbitrary
definition of polymorphism
•H can be computed directly from
knowledge of the allele frequencies
•H is not affected by sampling effects or
mating systems.
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Random genetic drift is an
anti-polymorphic force.
Gene diversity is expected to decrease
under random genetic drift.
In the absence of mutational input,
gene diversity will decrease by a
fraction of 1/2Ne each generation
(Ne = effective population size).
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h and H are unsuitable for DNA data, since the
extent of genetic variation at the DNA level in
nature is extensive, and both h and H will be
~1 in most cases. Thus, h and H will not be
informative measures of polymorphism. The
values of h and H is the same for both groups
of sequences above.
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Nucleotide Diversity (
Nucleotide Diversity = Average number of
nucleotide differences per site between two
randomly chosen sequences.
P   xi x j pij
ij
where xi and xj are the frequencies of the ith and jth
type of DNA sequences, respectively, and ij is the
proportion of different nucleotides between the ith
and jth types.
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The alcohol dehydrogenase locus in Drosophila melanogaster
Total number of compared sites = 2,379.
S = slow migrating electrophoretic allele.
F = fast migrating electrophoretic allele.
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Pairwise percent nucleotide differences among 11 alleles of
the alcohol dehydrogenase locus in Drosophila melanogaster.
Allele
1 S
1 S 2  S 3  S 4  S 5  S 6  S 7  F 8  F 9  F 10  F
2S
3S
4S
0.13
0.59
0.67
0.55
0.63
0.25
5 S
6 S
0.80
0.80
0.84
0.67
0.55
0.38
0.46
0.46
0.59
7F
8F
0.84
1.13
0.71
1.10
0.50
0.88
0.59
0.97
0.63
0.59
0.21
0.59
0.38
9  F 1.13
10  F 1.13
11  F 1.22
1.10
1.10
1.18
0.88
0.88
0.97
0.97
0.97
1.05
0.59
0.59
0.84
0.59
0.59
0.67
0.38
0.38
0.46
0.00
0.00
0.42
0.00
0.42
0.42
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Types of Genetic Variation:
Single nucleotide polymorphisms (SNPs) due to point
mutations.
Structural variation due to deletions, duplications,
insertions, inversions, and translocations.
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Types of Structural Genetic variation:
Submicroscopic variation (less than 3Mb).
Microscopic variation (more than 3Mb).
Copy number variants (CNVs) are submicroscopic
structural variations that are due to deletion, duplication,
and replicative transposition. If the variation in copy
number occurs in tandem, it is referred to as variable
number of tandem repeats (VNTRs).
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Types of Structural Genetic variation:
Inversion. A segment of DNA that is reversed in
orientation with respect to the rest of the chromosome.
Pericentric inversions include the centromere, whereas
paracentric inversions do not.
Translocation. A change in position of a chromosomal
segment within a genome that involves no change in total
DNA content. Translocations can be intra- or interchromosomal.
Segmental uniparental disomy. Uniparental disomy
describes the phenomenon in which a pair of homologous
chromosomes or portions of a chromosome in a diploid
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individual is derived from a single parent.
Which mammal has the most size variation?
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Which mammal has the most size variation?
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Human Genetic Variation
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With the exception of monozygotic
twins, which are NEARLY identical
genetically
every one of us is genetically
different from every other human
who ever lived.
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Geographic distribution of skin and hair color
Distribution of Human Skin Color
Clinal distribution of hair color among
Australian Aborigines
Discontinuous distribution of red
hair in Britain
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Genetic variation may be important
from a medical point of view
For example, because of genetic differences, different people may
respond differently to the same drug
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

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In the 1950s, anesthesiologists began using the muscle relaxant
succinylcholine
Succinylcholine is normally metabolized by cholinesterase
One out of 2,500 people are heterozygous for a variant of
cholinesterase that does not metabolize succinylcholine
These people are OK unless exposed to succinylcholine, in
which case they go into breathing arrest
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How are genomes of
individuals different from
one another?
More than 90% of the
differences are single base
substitutions. These are called
single nucleotide
polymorphisms (SNPs)
Nature 409, 822 - 823 (2001)
SNP
Any two human genomes are roughly 99.9% identical
chr - chromosome
n - Number of samples examined
S - Number of polymorphic sites
 - Nucleotide divergence
Mean = ~ 0.1%
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Przeworski, M., et al. (2000) Trends Genet 16, 296-302.
If (1) two genomes are roughly 99.9%
identical to each other, and (2) a haploid
genome is 3.2 billion base-pairs in length,
then, there are 3.2 million differences
(SNPs) between any two genomes.
(remember that each diploid
individual has two genomes)
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Kruglyak and Nickerson Nature Genetics (2001) 27 234
How many SNPs have been identified in humans?
Build 135, November 3, 2011
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Where are the SNPs found?
protein-coding exon
Total: 60,480,978 SNPs
In protein-coding exons: 862,465 SNPs (1.4%)
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http://www.ncbi.nlm.nih.gov/SNP/snp_summary.cgi
How many SNPs are “born” in each generation?
Number of genomes: N = 14×109 (twice the number of people)
Mutation rate:
m = ~2×10-8 per base-pair per generation
New mutations = Nm = 280 per base-pair per generation
Each nucleotide in the genome gets mutated on average in 280
individuals in each generation
The overwhelming majority of these will never attain polymorphic
status (arbitrarily set at 1% of the population)
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Kruglyak and Nickerson Nature Genetics (2001) 27 234
How are the frequencies of the SNPs distributed?
35,989 SNPs in a sample of 20 chromosomes 21.
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Patil et al. Science (2001) 294:1719-1723
Percentage of human genetic variation within and between populations.
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R.A.Brown,G.J.Armelagos,Evol.Anthropol.10 ,34 (2001).
Owens and King Science (1999) 286: 451-453.
Percentage of human genetic variation within and between populations.
An average population from anywhere in the world contains 85% of all human variation at
autosomal loci and 81% of all human variation in mtDNA sequences. Differences among
populations from the same continent contribute another 6% of variation; only 9-13% of 35
genetic
variation differentiates populations from different continents.
Most alleles are geographically widespread
377 autosomal microsallelite loci
1056 individuals from 52 populations from seven regions
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Rosenberg et al. Science Dec 20 2002: 2381-2385. (supplement)
There are non major genetic differences across ‘races’
= NO ‘races’
“The possibility that human
history has been characterized
by genetically relatively
homogeneous groups (‘races’),
distinguished by major biological
differences, is not consistent with
genetic evidence.”
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Owens and King. Science (1999) 286: 451-453.
Copy number variation (CNV) of DNA sequences in 270 individuals
from four populations with ancestry in Europe, Africa or Asia.
A total of 1,447 copy number variable regions (CNVRs), covering
360 megabases (12% of the genome) were identified in these
populations.
These CNVRs encompassed more nucleotide content per genome
than SNPs, underscoring the importance of CNV in genetic diversity
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and evolution.