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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 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 where xi frequency of allele i
and m total number of alleles at the locus. h
probability that two alleles chosen at random
from the population are different from each
other.
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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, 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. 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.
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S
F
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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
(Data for native populations collected by R.
Biasutti prior to 1940.)   
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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

• 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?
SNP
More than 90 of the differences are single base
substitutions. These are called single nucleotide
polymorphisms (SNPs)
Nature 409, 822 - 823 (2001)
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Any two human genomes are roughly 99.9 identical
Mean 0.1
Chr - chromosome n - Number of samples
examined bp - Number of basepairs sequences S -
Number of polymorphic sites p - Nucleotide
divergence
Przeworski, M., et al. (2000) Trends Genet 16,
296-302.
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If (1) two genomes are roughly 99.9 identical to
each other and (2) a genome is 3.2 billion
base-pairs in length, then, there are 3.2 million
differences (SNPs) between any two genomes.
(remember also that each individual has
two genomes)
Kruglyak and Nickerson Nature Genetics (2001) 27
234
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How many SNPs are born in each generation?
Number of genomes N 12109 (twice the number
of people) Mutation rate m
210-8 per base-pair per generation New
mutations Nm 240 per base-pair per
generation Each nucleotide gets mutated in 240
individuals in each generation The overwhelming
majority of these will never attain polymorphic
status (arbitrarily set at 1 of the population)
Kruglyak and Nickerson Nature Genetics (2001) 27
234
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How many SNPs are there in human populations?
Occurrence of SNPs in the human population
(based upon the neutral theory of molecular
evolution)
Kruglyak and Nickerson Nature Genetics (2001) 27
234
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How are the frequencies of the SNPs distributed?
35,989 SNPs in a sample of 20 chromosomes 21.
Patil et al. Science (2001) 2941719-1723
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Where are the SNPs found?
Most SNPs are found in the non-genic part of the
genome and are, consequently, inconsequential.
http//www.ncbi.nlm.nih.gov/SNP/snp_summary.cgi
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Derived from dbSNP release 119 http//www.ncbi.nlm
.nih.gov/SNP/
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Percentage of human genetic variation within and
between populations.
R.A.Brown,G.J.Armelagos,Evol.Anthropol.10 ,34
(2001).
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Percentage of human genetic variation within and
between populations.
Owens and King Science (1999) 286 451-453.
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 genetic variation
differentiates populations from different
continents.
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Most alleles are geographically widespread
377 autosomal microsallelite loci 1056
individuals from 52 populations from seven regions
Rosenberg et al. Science Dec 20 2002 2381-2385.
(supplement)
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No 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 . . .. The myth of major
genetic differences across races in nonetheless
worth dismissing with genetic evidence.
Owens and King Science (1999) 286 451-453.
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Some structural variants Copy-number variant
(CNV). Variable copy numbers of segments of DNA
that are 1 kb or longer. Classes of CNVs include
insertions, deletions and duplications. Also
included large-scale copy-number variants, which
are variants that involve segments of DNA greater
than 50 kb. 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 inter-chromosomal. Segmental
uniparental disomy. Uniparental disomy describes
the phenomenon in which a pair of homologous
chromosomes or portions of a chromosome in a
diploid individual is derived from a single
parent.
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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 and evolution.