Transcript lecture26_Polymorphi..

individuals 1-10
genetic variation is meaningful
only in the context of a population
ccagtcagagAtgtgcacatggcttagttttcatacaGagcctgggctgggggtggggtg
ccagtcagagAtgtgcacatggcttagttttcatacacagcctgggctgggggtggggtg
ccagtcagagttgtgcacatggcttagttttcatacacagcctgggctgggggtggggtg
ccagtcagagAtgtgcacatggcttagttttcatacacagcctgggctgggggtggggtg
ccagtcagagAtgtgcacatggcttagttttcatacacagcctgggctgggggtggggtg
ccagtcagagttgtgcacatggcttagttttcatacacagcctgggctCggggtggggtg
ccagtcagagttgtgcacatggcttagttttcatacacagcctgggctgggggtggggtg
ccagtcagagttgtgcacatgTcttagttttcatacacagcctgggctgggggtggggtg
ccagtcagagttgtgcacatggcttagttttcatacaGagcctgggctgggggtggggtg
ccagtcagagttgtgcacatggcttagttttcatacacagcctgggctgggggtggggtg
f = 4/10
f = 1/10
f = 2/10
f = 1/10
the minor allele frequency f says how often a particular allele (variant)
occurs at a particular site in a given population; by definition it is < 0.5
single nucleotide polymorphisms (SNPs) are essentially all biallelic; tri-allelic SNPs are very rare
two individuals vary about every 1000 bp; worldwide however
all but a few % of the genome is variable in somebody
most SNPs are evolutionarily neutral, in part because most of
the genome itself is non-functional
distributions of minor allele frequencies conform to a 1/[f·(1-f)]
formula, in accordance with neutral theory predictions
rare SNPs with smaller frequencies tend to be more recent in
origin and more population specific
most SNPs are at low frequency
# of SNPs found = 1541
# of SNPs
1000
NonSyn
Synon
5'-UTR
3'-UTR
Frame
Splice
5'-Flank
3'-Flank
Intron
750
500
250
0
0
0.1
0.2
0.3
0.4
f (minor allele)
0.5
this is the observed frequency distribution from the complete sequencing a large
population; however most SNP discovery projects sequence a small population
and then consider the absence or presence of those previously discovered SNPs
in large population; this is known to under-estimate the number of rare variants
higher variation in African relative to
European-American populations is
consistent with “Out of Africa” model
i.e., European-American populations grew out of African populations
Halushka MK, …, Chakravarti A. 1999. Nat Genet 22: 239-347
population specific SNPs are more
recent in origin and found at lower
allele frequency than shared SNPs
minor allele frequencies are classified by occurrence within individuals of either
African or European descent (population specific), or presence in both (shared)
Lewontin’s (in)famous paper on
non-existence of “race” in genetics
Lewontin RC. 1972. "The apportionment of human diversity“, in
Evolutionary Biology 6: 391-398
most of the variations (85%) found in human populations is found within
local geographic groups and any differences attributable to race groups is
just a small fraction of human genetic variability (15%); race is an invalid
taxonomic construct because the probability of a racial misclassification is
approximately 30% based on a single genetic locus
Edwards AW. 2003. Human genetic diversity: Lewontin's fallacy.
Bioessays 25: 798-801
even if the probability of misclassifying an individual’s race based on a
single locus is as high as 30%, the misclassification probability based on
10 loci can drop to a few percent
genetic structure of human populations
Africa
Europe
Asia
Rosenberg NA, …, Feldman MW. 2002. Science 298: 2381-2385
This analysis is based on 377 microsatellites in 1056 individuals from 52 populations. Variations
within populations account for 93 to 95% of the data. Nonetheless we can identify clusters that
are consistent with known populations. K is chosen in advance. For any given K, each individual
is represented by a thin vertical line, which is partitioned into K colored segments indicating the
individual’s estimated membership in the preordained K clusters.
BUT most of the genetic variation is within populations
genes and environment interact in
determination of phenotypic difference
Mountain JL, Risch N. 2004. Nat Genet 36: S48-S53.
(a) Absolute pitch manifests primarily in the group with early (before age 6) musical
training, is familial and may have a genetic component, but that genetic influence
does not manifest in the absence of early musical training. The difference is primarily
environmental. (b) Phenylthiocarbamide tasting gene (PTC) on chromosome 7 is
polymorphic in European populations, with the low-sensitivity haplotype at frequency
0.50 and the homozygotes at frequency 0.25. This haplotype is missing in Native
American populations. Hence the difference is primarily genetic.
the more politically controversial
traits are much more environmental
in nature and much less genetic
there is always a statistical distribution and so if we judge people as
individuals (unlike insurance companies) there would be no problem