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Background Large palindromes (inverted repeats) make up substantial proportions of mammalian sex chromosomes, often contain genes, and have high rates of structural variation arising via ectopic recombination. As a result, they underlie many genomic disorders. Maintenance of the palindromic structure by gene conversion between the arms has been documented, but over longer time periods, palindromes are remarkably labile. Mechanisms of origin and loss of palindromes have, however, received little attention. Results Here, we use fiber-FISH, 10x Genomics Linked-Read sequencing, and breakpoint PCR sequencing to characterize the structural variation of the P8 palindrome on the human Y chromosome, which contains two copies of the VCY (Variable Charge Y) gene. We find a deletion of almost an entire arm of the palindrome, leading to death of the palindrome, a size increase by recruitment of adjacent sequence, and other complex changes including the formation of an entire new palindrome nearby. Together, these changes are found in ~ 1% of men, and we can assign likely molecular mechanisms to these mutational events. As a result, healthy men can have 1–4 copies of VCY. Conclusions Gross changes, especially duplications, in palindrome structure can be relatively frequent and facilitate the evolution of sex chromosomes in humans, and potentially also in other mammalian species.

We present a new method, Fine-Mapping of Adaptive Variation (FineMAV), which combines population differentiation, derived allele frequency, and molecular functionality to prioritize positively selected candidate variants for functional follow-up. We calibrate and test FineMAV using eight experimentally validated “gold standard” positively selected variants and simulations. FineMAV has good sensitivity and a low false discovery rate. Applying FineMAV to the 1000 Genomes Project Phase 3 SNP dataset, we report many novel selected variants, including ones in TGM3 and PRSS53 associated with hair phenotypes that we validate using available independent data. FineMAV is widely applicable to sequence data from both human and other species. Electronic supplementary material The online version of this article (10.1186/s13059-017-1380-2) contains supplementary material, which is available to authorized users.

A report on the 'Genomic Disorders 2013: from 60 years of DNA to human genomes in the clinic' meeting, held at Homerton College, Cambridge, UK, April 10-12, 2013.

Genome-wide genotypes and sequences are enriching our understanding of the past 50,000 years of human history and providing insights into earlier periods largely inaccessible to mitochondrial DNA and Y-chromosomal studies. To see a world in a grain of sand ... William Blake, Auguries of Innocence

The number of coding genes in the human genome is still under debate [1]. Here, we present a proposal to define the human reference gene set that takes into account the inter-individual differences in gene numbers arising from gene inactivation events, such as premature termination or aberrant splicing due to nonsense SNPs or SNPs at essential splice sites respectively. We have analyzed SNPs (specifically nonsense SNPs and SNPs affecting essential splice sites) from 23 personal genomes and exomes. We see a wide range in numbers of SNPs in each of the categories surveyed. A large fraction of these SNPs are singletons. Using a data set of high-confidence SNPs obtained by intersecting SNPs from dbSNP and the personal genomes, we identify a common set of 279 genes predicted to be pseudogenic (non-functional) in some individuals and functional in others. We focused on two key questions arising from these considerations: (i) Which criteria should be used for inclusion and exclusion of genes from the reference set? (ii) What sequence should be used as the reference for genes that are non-functional in some humans? For the first question, we propose to include all genes that are functional even in one individual to produce a maximally-inclusive set of genes. For the second, we propose the use of the ancestral allele as the reference allele. This will provide a uniform basis for gene annotation and ensure that the reference gene set and sequence will be relatively stable as more individual genomes are sequenced. In the few cases where an ancestral state assignment is unavailable or ambiguous, we propose that genes be annotated as the functional allele.

Next-generation sequencing technologies have produced many 'whole' human genome sequences and the 1000 Genomes Project is poised to add two and a half thousand additional genomes. The 1000 Genomes Pilot 1 Project has sequenced Y chromosomes from 77 males (27 CEU, 10 CHB, 16 JPT, 24 YRI) albeit at low (1x-2x) sequence coverage, and identified a total of ~3000 variable sites of which 75% are novel. Although many sites are missed, preliminary validation by Sanger di-deoxy sequencing gave an initial estimate of a low (3.3%) false positive rate. In addition, we have developed a resource of Y-specific primer pairs that target single-copy regions of the human Y chromosome. These have been used to produce 5-7 kb overlapping fragments by long-PCR that are subsequently pooled and sequenced. This strategy was used to sequence, at high depth, 2-3 Mb of single-copy Y-specific DNA in a haplogroup A individual. The primer pairs have also been distributed to the wider community with the aim of re-sequencing comparable targeted regions in a diverse group of Y chromosomes. Using these primers, we have also established a tag indexing protocol that uses an 8-bp tag specific to each male, so that pooled samples from several males can be sequenced in one lane of an Illumina Genome Analyzer II, and sequence reads can be assigned back to each male sample using the tag. Using these approaches, we aim to generate individual Y-chromosomal sequences with adequate coverage that can be appropriately filtered to generate robust Y-SNP calls for refinement of the Y phylogenetic tree and further investigation of lineages of particular interest.

The second personal genome sequence of a Korean tells something about genetic ancestry but still little of medical relevance., The publication of the highest-quality and best-annotated personal genome yet tells us much about sequencing technology, something about genetic ancestry, but still little of medical relevance.

Ancient DNA research is revealing a human history far more complex than that inferred from parsimonious models based on modern DNA. Here, we review some of the key events in the peopling of the world in the light of the findings of work on ancient DNA.

Background Rare coding variants constitute an important class of human genetic variation, but are underrepresented in current databases that are based on small population samples. Recent studies show that variants altering amino acid sequence and protein function are enriched at low variant allele frequency, 2 to 5%, but because of insufficient sample size it is not clear if the same trend holds for rare variants below 1% allele frequency. Results The 1000 Genomes Exon Pilot Project has collected deep-coverage exon-capture data in roughly 1,000 human genes, for nearly 700 samples. Although medical whole-exome projects are currently afoot, this is still the deepest reported sampling of a large number of human genes with next-generation technologies. According to the goals of the 1000 Genomes Project, we created effective informatics pipelines to process and analyze the data, and discovered 12,758 exonic SNPs, 70% of them novel, and 74% below 1% allele frequency in the seven population samples we examined. Our analysis confirms that coding variants below 1% allele frequency show increased population-specificity and are enriched for functional variants. Conclusions This study represents a large step toward detecting and interpreting low frequency coding variation, clearly lays out technical steps for effective analysis of DNA capture data, and articulates functional and population properties of this important class of genetic variation.