Biology subjects

Chris Tyler-Smith

Publications and source records attributed to Chris Tyler-Smith.

8 recordsLinked to original sources

bioRxiv2016

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

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 x 10-8 per base pair per generation in autosomal coding sequence, with a corresponding noncrossover gene conversion rate of 8.75 {+/-} 0.05 x 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 5 CCG 3 [->] 5 CTG 3 context in the Pakistani population compared to Europeans, suggesting that mutational processes have evolved rapidly between human populations.

Genomics↗

bioRxiv2016

Population-Scale Sequencing Data Enables Precise Estimates of Y-STR Mutation Rates

Short Tandem Repeats (STRs) are mutation-prone loci that span nearly 1% of the human genome. Previous studies have estimated the mutation rates of highly polymorphic STRs using capillary electrophoresis and pedigree-based designs. While this work has provided insights into the mutational dynamics of highly mutable STRs, the mutation rates of most others remain unknown. Here, we harnessed whole-genome sequencing data to estimate the mutation rates of Y-chromosome STRs (Y-STRs) with 2-6 base pair repeat units that are accessible to Illumina sequencing. We genotyped 4,500 Y-STRs using data from the 1000 Genomes Project and the Simons Genome Diversity Project. Next, we developed MUTEA, an algorithm that infers STR mutation rates from population-scale data using a high-resolution SNP-based phylogeny. After extensive intrinsic and extrinsic validations, we harnessed MUTEA to derive mutation rate estimates for 702 polymorphic STRs by tracing each locus over 222,000 meioses, resulting in the largest collection of Y-STR mutation rates to date. Using our estimates, we identified determinants of STR mutation rates and built a model to predict rates for STRs across the genome. These predictions indicate that the load of de novo STR mutations is at least 75 mutations per generation, rivaling the load of all other known variant types. Finally, we identified Y-STRs with potential applications in forensics and genetic genealogy, assessed the ability to differentiate between the Y-chromosomes of father-son pairs, and imputed Y-STR genotypes.

Genomics↗

bioRxiv2015

Health and population effects of rare gene knockouts in adult humans with related parents

AbstractComplete gene knockouts are highly informative about gene function. We exome sequenced 3,222 British Pakistani-heritage adults with high parental relatedness, discovering 1,111 rare-variant homozygous likely loss of function (rhLOF) genotypes predicted to disrupt (knockout) 781 genes. Based on depletion of rhLOF genotypes, we estimate that 13.6% of knockouts are incompatible with adult life, finding on average 1.6 heterozygous recessive lethal LOF variants per adult. Linking to lifelong health records, we observed no association of rhLOF genotypes with prescription- or doctor-consultation rate, and no disease-related phenotypes in 33 of 42 individuals with rhLOF genotypes in recessive Mendelian disease genes. Phased genome sequencing of a healthy PRDM9 knockout mother, her child and controls, showed meiotic recombination sites localised away from PRDM9-dependent hotspots, demonstrating PRDM9 redundancy in humans.

Genomics↗

bioRxiv2015

Iron Age and Anglo-Saxon genomes from East England reveal British migration history

British population history has been shaped by a series of immigrations and internal movements, including the early Anglo-Saxon migrations following the breakdown of the Roman administration after 410CE. It remains an open question how these events affected the genetic composition of the current British population. Here, we present whole-genome sequences generated from ten ancient individuals found in archaeological excavations close to Cambridge in the East of England, ranging from 2,300 until 1,200 years before present (Iron Age to Anglo-Saxon period). We use present-day genetic data to characterize the relationship of these ancient individuals to contemporary British and other European populations. By analyzing the distribution of shared rare variants across ancient and modern individuals, we find that todays British are more similar to the Iron Age individuals than to most of the Anglo-Saxon individuals, and estimate that the contemporary East English population derives 30% of its ancestry from Anglo-Saxon migrations, with a lower fraction in Wales and Scotland. We gain further insight with a new method, rarecoal, which fits a demographic model to the distribution of shared rare variants across a large number of samples, enabling fine scale analysis of subtle genetic differences and yielding explicit estimates of population sizes and split times. Using rarecoal we find that the ancestors of the Anglo-Saxon samples are closest to modern Danish and Dutch populations, while the Iron Age samples share ancestors with multiple Northern European populations including Britain.

Genetics↗

bioRxiv2015

Genetic evidence for an origin of the Armenians from Bronze Age mixing of multiple populations

The Armenians are a culturally isolated population who historically inhabited a region in the Near East bounded by the Mediterranean and Black seas and the Caucasus, but remain underrepresented in genetic studies and have a complex history including a major geographic displacement during World War One. Here, we analyse genome-wide variation in 173 Armenians and compare them to 78 other worldwide populations. We find that Armenians form a distinctive cluster linking the Near East, Europe, and the Caucasus. We show that Armenian diversity can be explained by several mixtures of Eurasian populations that occurred between [~]3,000 and [~]2,000 BCE, a period characterized by major population migrations after the domestication of the horse, appearance of chariots, and the rise of advanced civilizations in the Near East. However, genetic signals of population mixture cease after [~]1,200 BCE when Bronze Age civilizations in the Eastern Mediterranean world suddenly and violently collapsed. Armenians have since remained isolated and genetic structure within the population developed [~]500 years ago when Armenia was divided between the Ottomans and the Safavid Empire in Iran. Finally, we show that Armenians have higher genetic affinity to Neolithic Europeans than other present-day Near Easterners, and that 29% of the Armenian ancestry may originate from an ancestral population best represented by Neolithic Europeans.

Genetics↗

bioRxiv2014

Expansion of the HSFY gene family in pig lineages

Amplified gene families on sex chromosomes can harbour genes with important biological functions, especially relating to fertility. The HSFY family has amplified on the Y chromosome of the domestic pig (Sus scrofa), in an apparently independent event to an HSFY expansion on the Y chromosome of cattle (Bos taurus). Although the biological functions of HSFY genes are poorly understood, they appear to be involved in gametogenesis in a number of mammalian species, and, in cattle, HSFY gene copy number correlates with levels of fertility.\n\nWe have investigated the HSFY family in domestic pigs, and other suid species including warthogs, bushpigs, babirusas and peccaries. The domestic pig contains at least two amplified variants of HSFY, distinguished predominantly by presence or absence of a SINE within the intron. Both these variants are expressed in testis, and both are present in approximately 50 copies each in a single cluster on the short arm of the Y. The longer form has multiple nonsense mutations rendering it likely non-functional, but many of the shorter forms still have coding potential. Other suid species also have these two variants of HSFY, and estimates of copy number suggest the HSFY family may have amplified independently twice during suid evolution. Given the association of HSFY gene copy number with fertility in cattle, HSFY is likely to play an important role in spermatogenesis in pigs also.

Genetics↗

bioRxiv2014

The pig X and Y chromosomes: structure, sequence and evolution

We have generated an improved assembly and gene annotation of the pig X chromosome, and a first draft assembly of the pig Y chromosome, by sequencing BAC and fosmid clones, and incorporating information from optical mapping and fibre-FISH. The X chromosome carries 1,014 annotated genes, 689 of which are protein-coding. Gene order closely matches that found in Primates (including humans) and Carnivores (including cats and dogs), which is inferred to be ancestral. Nevertheless, several protein-coding genes present on the human X chromosome were absent from the pig (e.g. the cancer/testis antigen family) or inactive (e.g. AWAT1), and 38 pig-specific X-chromosomal genes were annotated, 22 of which were olfactory receptors. The pig Y chromosome assembly focussed on two clusters of male-specific low-copy number genes, separated by an ampliconic region including the HSFY gene family, which together make up most of the short arm. Both clusters contain palindromes with high sequence identity, presumably maintained by gene conversion. The long arm of the chromosome is almost entirely repetitive, containing previously characterised sequences. Many of the ancestral X-related genes previously reported in at least one mammalian Y chromosome are represented either as active genes or partial sequences. This sequencing project has allowed us to identify genes - both single copy and amplified - on the pig Y, to compare the pig X and Y chromosomes for homologous sequences, and thereby to reveal mechanisms underlying pig X and Y chromosome evolution.

Genomics↗

bioRxiv2014

Human genomic regions with exceptionally high or low levels of population differentiation identified from 911 whole-genome sequences

BackgroundPopulation differentiation has proved to be effective for identifying loci under geographically-localized positive selection, and has the potential to identify loci subject to balancing selection. We have previously investigated the pattern of genetic differentiation among human populations at 36.8 million genomic variants to identify sites in the genome showing high frequency differences. Here, we extend this dataset to include additional variants, survey sites with low levels of differentiation, and evaluate the extent to which highly differentiated sites are likely to result from selective or other processes.\n\nResultsWe demonstrate that while sites of low differentiation represent sampling effects rather than balancing selection, sites showing extremely high population differentiation are enriched for positive selection events and that one half may be the result of classic selective sweeps. Among these, we rediscover known examples, where we actually identify the established functional SNP, and discover novel examples including the genes ABCA12, CALD1 and ZNF804, which we speculate may be linked to adaptations in skin, calcium metabolism and defense, respectively.\n\nConclusionsWe have identified known and many novel candidate regions for geographically restricted positive selection, and suggest several directions for further research.

Genomics↗