Detection of recent natural selection is a challenging problem in population genetics. Here we introduce the singleton density score (SDS), a method to infer very recent changes in allele frequencies from contemporary genome sequences. Applied to data from the UK10K Project, SDS reflects allele frequency changes in the ancestors of modern Britons during the past ~2000 to 3000 years. We see strong signals of selection at lactase and the major histocompatibility complex, and in favor of blond hair and blue eyes. For polygenic adaptation, we find that recent selection for increased height has driven allele frequency shifts across most of the genome. Moreover, we identify shifts associated with other complex traits, suggesting that polygenic adaptation has played a pervasive role in shaping genotypic and phenotypic variation in modern humans.

https://science.sciencemag.org/content/sci/early/2016/10/12/science.aag0776.full.pdf

Detection of human adaptation during the past 2000 years

DNA is a molecule that contains the information needed to build an organism This information is stored as a code made up of four chemicals: adenine (A), guanine (G), cytosine (C), and thymine (T) Every time a cell divides and copies its DNA, it accidentally introduces ‘typos’ into the code, known as mutations Most mutations are harmless, but some can cause damage All cells have ways to proofread DNA, and the more resources are devoted to proofreading, the less mutations occur Simple organisms such as bacteria use less energy to reduce mutations, because their genomes may tolerate more damage More complex organisms, from yeast to humans, instead need to proofread their genomes more thoroughly Recent research has shown that humans have a lower mutation rate than chimpanzees and gorillas, their closest living relatives Humans and other apes copy and proofread their DNA with basically the same biological machinery as yeast, which is about a billion years old Yet, humans and apes have only existed for a small fraction of this time, a few million years Why then do humans need to replicate and proofread their DNA differently from apes, and could it be that the way mutations arise is still evolving? Previous research revealed that European people experience more mutations within certain DNA motifs (specifically, the DNA sequences ‘TCC’, ‘TCT’, ‘CCC’ and ‘ACC’) than Africans or East Asians do Now, Harris (who conducted the previous research) and Pritchard have compared how various human ethnic groups accumulate mutations and how these processes differ in different groups Statistical analysis of the genomes of thousands of people from all over the world did indeed show that the mutation rates of many different three-letter DNA motifs have changed during the past 20,000 years of human evolution Harris and Pritchard report that when groups of humans left Africa and settled in isolated populations across different continents, each population quickly became better at avoiding mutations in some genomic contexts, but worse in others This suggests that the risk of passing on harmful mutations to future generations is changing and evolving at an even faster rate than was originally suspected The results suggest that every human ethnic group carries specific variants of the genes which ensure that DNA replication and repair are accurate These differences appear to influence which types of mutations are frequently passed down to future generations An important next step will be to identify the genetic variants that could be controlling mutational patterns and how they affect human health

/pdf/rapid-evolution-of-the-human-mutation-spectrum-17w649dy6p.pdf

Rapid evolution of the human mutation spectrum

Two decades ago, the sequence of the first human genome was published. Since then, advances in genome technologies have resulted in whole-genome sequencing and microarray-based genotyping of millions of human genomes. However, genetic and genomic studies are predominantly based on populations of European ancestry. As a result, the potential benefits of genomic research—including better understanding of disease etiology, early detection and diagnosis, rational drug design and improved clinical care—may elude the many underrepresented populations. Here, we describe factors that have contributed to the imbalance in representation of different populations and, leveraging our experiences in setting up genomic studies in diverse global populations, we propose a roadmap to enhancing inclusion and ensuring equal health benefits of genomics advances. Our Perspective highlights the importance of sincere, concerted global efforts toward genomic equity to ensure the benefits of genomic medicine are accessible to all. 

/pdf/a-roadmap-to-increase-diversity-in-genomic-studies-2z8lry14.pdf

A roadmap to increase diversity in genomic studies

https://www.repository.cam.ac.uk/bitstream/1810/257350/1/Scally-2016-Current_Opinion_in_Genetics_%26_Development-AM.pdf

The mutation rate in human evolution and demographic inference.

Meiotic recombination involves a combination of gene conversion and crossover events that, along with mutations, produce germline genetic diversity. Here we report the discovery of 3,176 SNP and 61 indel gene conversions. Our estimate of the non-crossover (NCO) gene conversion rate (G) is 7.0 for SNPs and 5.8 for indels per megabase per generation, and the GC bias is 67.6%. For indels, we demonstrate a 65.6% preference for the shorter allele. NCO gene conversions from mothers are longer than those from fathers, and G is 2.17 times greater in mothers. Notably, G increases with the age of mothers, but not the age of fathers. A disproportionate number of NCO gene conversions in older mothers occur outside double-strand break (DSB) regions and in regions with relatively low GC content. This points to age-related changes in the mechanisms of meiotic gene conversion in oocytes.

/pdf/the-rate-of-meiotic-gene-conversion-varies-by-sex-and-age-2yfo1uozug.pdf

The rate of meiotic gene conversion varies by sex and age.

Heterozygous mutations within homozygous sequences descended from a recent common ancestor offer a way to ascertain de novo mutations (DNMs) across multiple generations. Using exome sequences from 3,222 British-Pakistani individuals with high parental relatedness, we estimate a mutation rate of 1.45 ± 0.05 × 10 -8 per base pair per generation in autosomal coding sequence, with a corresponding non-crossover gene conversion rate of 8.75 ± 0.05 × 10 -6 per base pair per generation. This is at the lower end of exome mutation rates previously estimated in parent-offspring trios, suggesting that post-zygotic mutations contribute little to the human germline mutation rate. We found frequent recurrence of mutations at polymorphic CpG sites, and an increase in C to T mutations in a 59 CCG 39 → 59 CTG 39 context in the Pakistani population compared to Europeans, suggesting that mutational processes have evolved rapidly between human populations.

/pdf/a-direct-multi-generational-estimate-of-the-human-mutation-257fgq45a5.pdf

A direct multi-generational estimate of the human mutation rate from autozygous segments seen in thousands of parentally related individuals

Background Individuals with South Asian ancestry have higher risk of heart disease than other groups in Western countries; however, most genetic research has focused on European-ancestry (EUR) individuals. It is unknown whether reported genetic loci and polygenic scores (PGSs) for cardiometabolic traits are transferable to South Asians, and whether PGSs have utility in clinical settings. Methods Using data from 22,000 British Pakistani and Bangladeshi individuals with linked electronic health records from the Genes & Health cohort (G&H), we conducted genome-wide association studies (GWAS) and characterised the genetic architecture of coronary artery disease (CAD), body mass index (BMI), lipid biomarkers and blood pressure. We applied a new technique to assess the extent to which loci from GWAS in EUR samples were transferable. We tested how well existing findings from EUR studies performed in genetic risk prediction and Mendelian randomisation in G&H. Results Trans-ancestry genetic correlations between GH 95% CI 0.9–7.0) when adding a previously developed CAD PGS to clinical risk factors (QRISK3). We used transferable loci as genetic instruments in trans-ancestry Mendelian randomisation and found evidence of an increased CAD risk for higher LDL-C and BMI, and for lower HDL-C in G&H, consistent with our findings for EUR samples. Conclusions The genetic loci for CAD and its risk factors are largely transferable from EUR studies to British Pakistanis and Bangladeshis, whereas the transferability of PGSs varies greatly between traits. Our analyses suggest clinical utility for addition of PGS to existing clinical risk prediction tools for this population. Clinical Perspective What is new? This is the first study to explore the transferability of GWAS findings and PGSs for CAD and related cardiometabolic traits in British Pakistani and Bangladeshi individuals from a cohort with real-world electronic clinical data. We propose a new approach to assessing transferability of GWAS loci between populations, which can serve as a new methodological standard in this developing field. We find evidence of overall high transferability of GWAS loci in British Pakistanis and Bangladeshis. BMI, lipids and blood pressure show the highest transferability of loci, and CAD the lowest. The transferability of PGSs varied between traits, being high for HDL-C, triglycerides and blood pressure but more modest for CAD, BMI and LDL-C. Our results suggest that, for some traits, the use of transferable GWAS loci improves the robustness of Mendelian randomisation estimates in non-Europeans. What are the clinical implications? The polygenic score for CAD derived from genetic studies of European individuals improves reclassification on top of clinical risk factors in British Pakistanis and Bangladeshis. The improvement was driven by identification of more cases in younger individuals (25–54 years old), and of controls in older individuals (55–84 years old). Incorporation of the polygenic score for CAD into risk prediction models is likely to prevent cardiovascular events and deaths in this population.

/pdf/transferability-of-genetic-loci-and-polygenic-scores-for-5fdkowg41y.pdf

van Heel Da

Papers

A direct multi-generational estimate of the human mutation rate from autozygous segments seen in thousands of parentally related individuals

Transferability of genetic loci and polygenic scores for cardiometabolic traits in British Pakistanis and Bangladeshis