Wednesday, February 20, 2008

Europeans are mutants and Oceanians have a lot of CNVs

Two new papers in Nature on global patterns in human genetics. Aren't I getting better at writing catchy, shocking titles for my posts? The first one is about the distribution of deleterious mutations in Europeans and Africans (Europeans, they find, have more):
from that one, I like this passage:
... the importance of adaptations for the evolution of European populations needs to be tempered by our finding that negative selection is less effective at removing slightly deleterious alleles from European populations. Second, the idea that bottlenecks and founder effects could lead to an increase in damaging alleles in human populations was historically reserved for isolated populations that experienced severe founder effects (for example Ashkenazi Jews22 and Finns23).
the second one uses a combination of 1/2 million SNPs and 396 CNVs to examine patterns of global variation from 29 populations. There's plenty of colorful eye candy figures in this one. I'm busy now so can't look too closely at either of these papers, but I'm intrigued by the finding of more CNVs in Oceania??? they probably have some kind of interpretation in the paper. If you read the paper and understand, please feel free to explain in the comments.

Proportionally more deleterious genetic variation in European than in African populations
Kirk E. Lohmueller, Amit R. Indap, Steffen Schmidt, Adam R. Boyko, Ryan D. Hernandez, Melissa J. Hubisz, John J. Sninsky, Thomas J. White, Shamil R. Sunyaev, Rasmus Nielsen, Andrew G. Clark & Carlos D. Bustamante
Nature 451, 994-997 (21 February 2008)
Abstract Quantifying the number of deleterious mutations per diploid human genome is of crucial concern to both evolutionary and medical geneticists1, 2, 3. Here we combine genome-wide polymorphism data from PCR-based exon resequencing, comparative genomic data across mammalian species, and protein structure predictions to estimate the number of functionally consequential single-nucleotide polymorphisms (SNPs) carried by each of 15 African American (AA) and 20 European American (EA) individuals. We find that AAs show significantly higher levels of nucleotide heterozygosity than do EAs for all categories of functional SNPs considered, including synonymous, non-synonymous, predicted 'benign', predicted 'possibly damaging' and predicted 'probably damaging' SNPs. This result is wholly consistent with previous work showing higher overall levels of nucleotide variation in African populations than in Europeans4. EA individuals, in contrast, have significantly more genotypes homozygous for the derived allele at synonymous and non-synonymous SNPs and for the damaging allele at 'probably damaging' SNPs than AAs do. For SNPs segregating only in one population or the other, the proportion of non-synonymous SNPs is significantly higher in the EA sample (55.4%) than in the AA sample (47.0%; P lesss than 2.3 times 10-37). We observe a similar proportional excess of SNPs that are inferred to be 'probably damaging' (15.9% in EA; 12.1% in AA; P less than 3.3 times 10-11). Using extensive simulations, we show that this excess proportion of segregating damaging alleles in Europeans is probably a consequence of a bottleneck that Europeans experienced at about the time of the migration out of Africa.
Genotype, haplotype and copy-number variation in worldwide human populations
Mattias Jakobsson, Sonja W. Scholz, Paul Scheet, J. Raphael Gibbs, Jenna M. VanLiere, Hon-Chung Fung, Zachary A. Szpiech, James H. Degnan, Kai Wang, Rita Guerreiro, Jose M. Bras, Jennifer C. Schymick, Dena G. Hernandez, Bryan J. Traynor, Javier Simon-Sanchez, Mar Matarin, Angela Britton, Joyce van de Leemput, Ian Rafferty, Maja Bucan, Howard M. Cann, John A. Hardy, Noah A. Rosenberg & Andrew B. Singleton
Nature 451, 998-1003 (21 February 2008)
Abstract Genome-wide patterns of variation across individuals provide a powerful source of data for uncovering the history of migration, range expansion, and adaptation of the human species. However, high-resolution surveys of variation in genotype, haplotype and copy number have generally focused on a small number of population groups1, 2, 3. Here we report the analysis of high-quality genotypes at 525,910 single-nucleotide polymorphisms (SNPs) and 396 copy-number-variable loci in a worldwide sample of 29 populations. Analysis of SNP genotypes yields strongly supported fine-scale inferences about population structure. Increasing linkage disequilibrium is observed with increasing geographic distance from Africa, as expected under a serial founder effect for the out-of-Africa spread of human populations. New approaches for haplotype analysis produce inferences about population structure that complement results based on unphased SNPs. Despite a difference from SNPs in the frequency spectrum of the copy-number variants (CNVs) detected—including a comparatively large number of CNVs in previously unexamined populations from Oceania and the Americas—the global distribution of CNVs largely accords with population structure analyses for SNP data sets of similar size. Our results produce new inferences about inter-population variation, support the utility of CNVs in human population-genetic research, and serve as a genomic resource for human-genetic studies in diverse worldwide populations.


n said...

From the paper:

However, some bias may exist in
CNV detection; as a result of difficulties in detecting high-frequency
CNVs from comparisons against reference intensities24, the absence
from the reference panel of Kalash and populations from Oceania
and the Americas may have increased the potential for identifying
CNVs in these groups
. In such distinctive populations, unusual
intensity signals for deletions or duplications are less likely to have
been diluted by inclusion in the reference panel of individuals with an
atypical copy number.

Yann Klimentidis said...

thank you. I'm not sure I get it. I probably need to look more closely at how exactly they're ascertaining and typing cnvs and the distribution of the populations.

Anonymous said...

Yann, can you in some detail explain Figure 3 from the nature paper?

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