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Specific projects:
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Linkage disequilibrium extends across putative selected sites in
FOXP2 Susan E. Ptak, Wolgang
Enard, Victor Wiebe, Ines Hellmann, Johannes Krause, Michael Lachmann, Svante Pääbo Molecular Biology and
Evolution (2009) Polymorphism data in humans suggest that the gene encoding the transcription factor FOXP2, which influences speech and language development, has been subject to a selective sweep within the last 260,000 years. It has been proposed that one or both of two substitutions that occurred on the human evolutionary lineage and changed amino acids were the targets for selection. In apparent contradiction to this is the observation that these substitutions are present in Neandertals who diverged from humans maybe 300,000-400,000 years ago. We have collected polymorphism data upstream and downstream of the substitutions. Contrary to what is expected following a selective sweep, we find that the haplotypes extend across the two sites. We discuss possible explanations for these observations. One of them is that the selective sweep reflected in FOXP2 polymorphism data was not associated with the two amino acid substitutions. |
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Combining sperm typing and linkage
disequilibrium analyses reveals differences in selective pressures or
recombination rates across human populations. Vanessa J. Clark, Susan E. Ptak, Irene Tiemann,
Yudong Qian, Graham Coop, Anne C. Stone, Molly Przeworski, Norman Arnheim,
Anna Di Rienzo Genetics 175: 795–804 (2007) A previous polymorphism
survey of the type 2 diabetes gene CAPN10 identified a segment showing an
excess of polymorphism levels in all population samples, coinciding with
localized breakdown of linkage disequilibrium (LD) in a sample of Hausa from
Cameroon, but not in non-African samples. This raised the possibility that a
recombination hotspot is present in all populations and we had insufficient
power to detect it in the non-African data. To test this possibility, we
estimated the crossover rate by sperm typing in five non-African men; these
estimates were consistent with the LD decay in the non-African, but not in
the Hausa data. Moreover, resequencing the orthologous region in a sample of
Western chimpanzees did not show either an excess of polymorphism level or
rapid LD decay, suggesting that the processes underlying the patterns
observed in humans operated only on the human lineage. These results suggest
that a hotspot of recombination has recently arisen in humans and has reached
higher frequency in the Hausa than in non Africans, or that there is no
elevation in crossover rate in any human population, and the observed
variation results from long-standing balancing selection. |
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Analysis
of one million base pairs of Neanderthal DNA. Richard
E. Green, Johannes Krause, Susan E. Ptak, AdrianW. Briggs, Michael T. Ronan,
Jan F. Simons, Lei Du, Michael Egholm, Jonathan M. Rothberg, Maja Paunovic,
Svante Pääbo Neanderthals
are the extinct hominid group most closely related to contemporary humans, so
their genome offers a unique opportunity to identify genetic changes specific
to anatomically fully modern humans.We have identified a 38,000-year-old
Neanderthal fossil that is exceptionally free of contamination from modern human
DNA. Direct high-throughput sequencing of a DNA extract from this fossil has
thus far yielded over one million base pairs of hominoid nuclear DNA
sequences. Comparison with the human and chimpanzee genomes reveals that
modern human and Neanderthal DNA sequences diverged
on average about 500,000 years ago. Existing technology and fossil resources
are now sufficient to initiate a Neanderthal genome-sequencing effort. pdf |
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Why do
human diversity levels vary at a megabase scale? Levels of diversity vary
across the human genome. This variation is caused by two forces: differences
in mutation rates and the differential impact of natural selection. Pertinent
to the question of the relative importance of these two forces is the
observation that both diversity within species and interspecies divergence
increase with recombination rates. This suggests that mutation and
recombination are either directly coupled or linked through some third
factor. Here, we test these possibilties using the recently generated
sequence of the chimpanzee genome and new estimates of human diversity. We
find that measures of GC and CpG content, simple-repeat structures, as well
as the distance from centromeres and the telomeres predict diversity as well
as divergence. After controlling for these factors, large-scale recombination
rates measured from pedigrees are still significant predictors of human
diversity and human-chimpanzee divergence. Furthermore, the correlation between
human diversity and recombination remains significant even after controlling
for human-chimpanzee divergence. Two plausible and non-mutually exclusive
explanations are, first, that natural selection has shaped the patterns of
diversity seen in humans, and second, that recombination rates across the
genome have changed since humans and chimpanzees shared a common ancestor, so
that current recombination rates are a better predictor of diversity than
divergence. Because there are indications that recombination may have
changed rapidly during human evolution, we favor the latter explanation. |
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Fine-scale
recombination patterns differ between chimpanzees and humans Recombination rates seem to
vary extensively along the human genome. Pedigree analysis suggests
that rates vary by an order of magnitude when measured at the megabase scale,
and at a finer scale, sperm typing studies point to the existence of
recombination hotspots. These are short regions (1-2 kb) in which
recombination rates are 10-1000 times higher than the background rate. Less
is known about how recombination rates change over time. Here we determine to
what degree recombination rates are conserved among closely related species
by estimating recombination rates from 14 Mb of linkage disequilibrium data
in central chimpanzee and human populations. The results suggest that
recombination hotspots are not conserved between the two species and that
recombination rates in larger (50 kb) genomic regions are only weakly
conserved. Therefore, the recombination landscape has changed markedly
between the two species. |
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Absence of the TAP2 human recombination
hotspot in chimpanzees Recent
experiments using sperm typing have demonstrated that, in several regions of
the human genome, recombination does not occur uniformly but instead is
concentrated in ‘‘hotspots’’ of 1–2 kb.
Moreover, the crossover asymmetry observed in a subset of these has led to
the suggestion that hotspots may be short-lived on an evolutionary time
scale. To test this possibility, we focused on a region known to contain a
recombination hotspot in humans, TAP2, and asked whether chimpanzees, the
closest living evolutionary relatives of humans, harbor a hotspot in a
similar location. Specifically, we used a new statistical approach to
estimate recombination rate variation from patterns of linkage disequilibrium
in a sample of 24 western chimpanzees (Pan troglodytes verus). This method
has been shown to produce reliable results on simulated data and on human
data from the TAP2 region. Strikingly, however, it finds very little support
for recombination rate variation at TAP2 in the western chimpanzee data.
Moreover, simulations suggest that there should be stronger support if there
were a hotspot similar to the one characterized in humans. Thus, it appears
that the human TAP2 recombination hotspot is not shared by western
chimpanzees. These findings demonstrate that fine-scale recombination rates
can change between very closely related species and raise the possibility
that rates differ among human populations, with important implications for
linkage-disequilibrium based association studies. |
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Insights into recombination from patterns of linkage
disequilibrium in humans An
ability to predict levels of linkage disequilibrium (LD) between linked
markers would facilitate the design of association studies and help to
distinguish between evolutionary models. Unfortunately, levels of LD depend
crucially on rates of recombination, a parameter that is difficult to
measure. In humans, rates of genetic exchange between markers megabases apart
can be estimated from a comparison of genetic and physical maps; these
large-scale estimates can then be interpolated to predict LD at smaller
("local") scales. However, if there is extensive small-scale
heterogeneity, as has been recently proposed, local rates of recombination
could differ substantially from those averaged over much larger distances. We
test this hypothesis by estimating local recombination rates indirectly from
patterns of LD in 84 genomic regions surveyed by the SeattleSNPs project in a
sample of individuals of European descent and of African-Americans. We find
that LD-based estimates are significantly positively correlated with
map-based estimates. This implies that large-scale, average rates are
informative about local rates of recombination. Conversely, although LD-based
estimates are based on a number of simplifying assumptions, it appears that
they capture considerable information about the underlying recombination
rate, or at least about the ordering of regions by recombination rate. Using
LD-based estimators, we also find evidence for homologous gene conversion in
patterns of polymorphism. However, as we demonstrate by simulation,
inferences about gene conversion are unreliable, even with extensive data
from homogeneous regions of the genome, and are confounded by genotyping
error. |
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Mutation and
recombination are associated processes in humans. |
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Evidence for population growth
in humans is confounded by fine-scale population structure Although many studies have reported human
polymorphism data, there has been no analysis of the effect of sampling design
on the patterns of variability recovered. Here, we consider which
factors affect a summary of the allele frequency spectrum. The most important
variable to emerge from our analysis is the number of ethnicities sampled:
studies that sequence individuals from more ethnicities recover more rare
alleles. These observations are consistent with fine-scale geographic
differentiation as well as population growth. They suggest that the
geographic sampling strategy should be considered carefully, especially when
the aim is to infer the demographic history of humans.
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How intron splicing
affects the insertion and deletion profile in Drosophila melanogaster Studies of "dead-on-arrival" transposable elements in Drosophila
melanogaster found that deletions outnumber insertions ~ 8:1 with a
median size for deletions of ~10 bp. These results are consistent with the
deletion and insertion profiles found in most other Drosophila pseudogenes.
In contrast, a recent study of D. melanogaster introns
found a deletion/insertion ratio of 1.35:1, with 84% of deletions being
shorter than 10 bp. This discrepancy could be explained if deletions,
especially long deletions, are more frequently strongly deleterious than
insertions and are eliminated disproportionately from intron sequences.
To test this possibility, we use analysis and simulations to examine
how deletions and insertions of different lengths affect different components
of splicing and determine the distribution of deletions and insertions that
preserve the original exons. We find that, consistent with our
predictions, longer deletions affect splicing at a much higher rate compared
to insertions and short deletions. We also explore other potential
constraints in introns and show that most of these also disproportionately
affect large deletions. Altogether we demonstrate that constraints in
introns may explain much of the difference in the pattern of deletions and
insertions observed in Drosophila introns and pseudogenes. |
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On the evolution of
polygamy: a theoretical examination of the polygamy threshold model The polygany threshold model states that if costs
incurred are less than the benefits gained from mating polygynously in
terms of male breeding-situation quality, then polygyny is favored and could
evolve. We constructed mathematical models and computer simulations to
evaluate this hypothesis. In the basic model, there is a single locus
with two alleles, which regulates whether the female is receptive to
polygyny. There are two breeding situations of differing quality on
which males randomly assort. Females then select a mate based on the
associated breeding situation and whether the male already has mates.
This basic model is extended mathematically to include cost for the
initial female of a male with multiple mates and again to include gene
expression in males. The computer simulations extend the basic model to
multiple loci and alleles, and to multiple breeding situations. The
results presented here suggest that the polygyny threshold model is valid in
a population genetic context: if the fitness of females that actually mated
polygynously is greater than the fitness of monogamous females on poorer
breeding situations, polygyny evolves. However, this approach reveals
interesting dynamics not apparent from the verbal model. If the trait
is expressed in males and females, then polygyny can evolve even if females
mating polygynously have a lower fitness than females mating monogamously.
In the multiple breeding-situations model, the polygyny allele
increases to some equilibrium value above which it experiences no
selection. Surprisingly, as the cost to polygyny increases, the
equilibrium value of the polygyny allele also increases. The difference
between this evolutionary model and the ideal free distribution is discussed. |
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The maintenance of
single-locus polymorphism. V. Sex-dependent viabilities. Since natural selection requires variation to act, the amount of
genetic variation in a given population is of central theoretical and
experimental importance. This amount is estimated by the genetic
variation present in current populations. Electrophoretic studies of
natural populations reveal that ten to twenty percent of all loci have
multiple alleles. These multi-allelic loci may be the result of the
accumulation of unselected mutations (neutral theory) or of balancing
selection (selectionist theory). The neutral theory views selection as
primarily eliminating variation,whereas the selectionist theory views
selection as often maintaining variation. Therefore, our view of
selection and evolution depends upon the question of how multiple allelic
systems evolve. To address whether
balancing selection increases genetic variation, we examined Owen's model in
which selection varies in the two sexes (sex-dependent model) and compared it
to a model in which selection is constant across the two sexes (sex-independent
model). We explored these models for a single multi-allelic locus to explore
more generally the effect of balancing selection on the maintenance and
construction of multi-allelic systems. To do so, we constructed two
computer models. The "fitness-space"approach examines the
proportion of all possible fitnesses capable of maintaining different sized
allelic systems. The proportion of possible fitnesses is greater in
balancing selection models. The"constructionist" approach
examines the ease in reaching this portion of possible fitnesses. The
ease in reaching fitnesses is less in balancing selection models. Thus,
in contrast to previous hypotheses, our research suggests that balancing
selection may not increase the amount of variation present in natural
populations. |
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