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Stanford’s Carlos Bustamante and his colleagues analyzed the genomes and exomes of seven geographically divergent human populations — from Namibia, Congo, Algeria, Pakistan, Cambodia, Siberia, and Mexico — and found that while the number of deleterious alleles in each individual varies only a little, classes of deleterious alleles show different patterns across those populations. These patterns seem to stem from the interaction of genetic drift and purifying selection, as the researchers reported in the Proceedings of the National Academy of Sciences this week.

“By directly ascertaining genomic variation in over 50 individuals from seven populations, we observe a clear cline of genetic diversity as a function of distance from Africa, supporting evidence for a serial founder effect model,” Bustamante and his colleagues wrote in their paper. “We also observe differences in the amount of predicted deleterious variation across populations.”

The researchers drew on a dataset of moderate, median 7X depth coverage whole-genome sequence and high, median 78X depth coverage exome sequence data from unrelated people belonging to seven populations represented in the Human Genome Diversity Panel.

Heterozygosity, the researchers found, decreases among the seven populations with increasing geographical distance from southern Africa. For instance, they noted that the Namibian San population harbored the highest amount of derived heterozygotes, about 2.39 million per sample, as compared to about 1.5 million among the Maya in Mexico.

This decline in heterozygosity with distance from Africa, they said, supports earlier SNP array- and microsatellite-based work that suggested a serial founder effect model for the ancestral populations of Eurasia, Oceania, and the Americas.

Using a pairwise sequential Markovian coalescent software-based analysis, the researchers further found that the out-of-Africa populations experienced a deep decline in effective population size, as previous analyses had also indicated.

Based on their Genomic Evolutionary Rate Profiling (GERP) Rejected Substitution scores, Bustamante and his colleagues classified the mutations they uncovered in the exome dataset into one of four categories, reflecting the projected severity of their effects. From this, the researchers found that the number of predicted deleterious alleles per individual increased with geographical distance from Africa, a pattern that is also consistent with serial bottlenecks or founder effects. The average, additive GERP score ranged from about 3.3 in the San to about 3.8 in the Maya, they added.

At the same time, Bustamante and his colleagues reported that there was no difference in putatively moderate or extremely deleterious effect variants between African and out-of-Africa populations in terms of the number of mutations per individual.

Using a new statistic they developed called RH that measures the reduction in heterozygosity at conserved sites as compared to neutral heterozygosity, Bustamante and his team examined how evolutionary forces acted on different human populations to shape their patterns of genetic diversity. A constant RH value, for instance, reflects genetic drift and migration, while a changing RH implies selection.

In their dataset, they found that RH is much larger among sub-Saharan Africans that in out-of-Africa populations for all functional GERP categories, indicating that selection has acted differently relative to drift on these two groups. This, they added, indicates that purifying selection has kept strongly deleterious alleles at lower frequency in African versus out-of-Africa populations.

Further, the out-of-Africa RH values for moderate-effect alleles don’t depend on their geographical distance from Africa, suggesting that such moderate mutations evolved according to neutral demographic processes during the expansion out of Africa.

Meanwhile, the researchers noted a cline in RH values for deleterious variants with distance from Africa that they said is consistent with unequal purging of deleterious variants by selection after they experienced drift during the out-of-Africa expansion.

Further, in a model in which selection was inversely related to dominance — most large-effect variants are recessive — Bustamante and his colleagues found that out-of-Africa populations are more likely to have a higher mutation load because of increased allele frequencies of recessive or partially recessive neutral variants.

“Whereas previous comparisons between African and non-African diversity attributed the observed increased proportion of deleterious variants in non-Africans to the [out-of-Africa] bottleneck, our study shows that a single bottleneck is not sufficient to reproduce the gradient we observe in the number of deleterious alleles per individual with distance from Africa,” the researchers added.

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Here we describe the SweGen dataset, a high-quality map of genetic variation in the Swedish population. This data represents a basic resource for clinical genetics laboratories as well as for sequencing-based association studies, by providing information on the frequencies of genetic variants in a cohort that is well matched to national patient cohorts.

To select samples for this study, we first examined the genetic structure of the Swedish population using high-density SNP-array data from a nation-wide population based cohort of over 10,000 individuals. From this sample collection, 1,000 individuals, reflecting a cross-section of the population and capturing the main genetic structure, were selected for whole genome sequencing (WGS).

Analysis pipelines were developed for automated alignment, variant calling and quality control of the sequencing data. This resulted in a whole-genome map of aggregated variant frequencies in the Swedish population that we hereby release to the scientific community.

Adam Ameur, Johan Dahlberg, Pall Olason, Francesco Vezzi, Robert Karlsson, Par Lundin, Huiwen Che, JessadaThutkawkorapin, Andreas Kusalananda Kahari, Mats Dahlberg, Johan Viklund, Jonas Hagberg, Niclas Jareborg,Inger Jonasson, Asa Johansson, Sverker Lundin, Daniel Nilsson, Bjorn Nystedt, Patrik Magnusson, Ulf Gyllensten