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Human Y-chromosome variation in the genome-sequencing era

Key Points

  • As a consequence of its key role in male sex determination, the Y chromosome has unique genetic properties that lead to it carrying highly informative haplotypes that evolve largely through the simple accumulation of mutations.

  • Advances in technology have allowed ~10 Mb of Y-chromosome DNA to be sequenced from large population samples, with consequent unbiased ascertainment of their genetic variation.

  • Y-Chromosome sequences can be assembled into a robust phylogeny, which can be calibrated using estimates of the mutation rate from family studies, known archaeological events or ancient DNA samples.

  • The calibrated Y-chromosome phylogeny reveals male expansions corresponding to the migration of modern humans out of Africa ~60,000 years ago, the colonization of the Americas ~15,000 years ago and more recent technology-driven population expansions.

  • The Y chromosome has a particularly important role in forensic genetics, as it allows male-specific DNA profiles to be compared at an increasingly high resolution.

  • In genealogical studies, the male-line inheritance of the Y chromosome makes it a perfect tool for studies of male family history, which has led to a burgeoning area of citizen science.

  • The Y chromosome is central to disorders of sex determination and spermatogenesis. Recently, mosaic somatic loss of the Y chromosome in ageing men has been associated with an increased risk of cancer mortality and Alzheimer disease.

Abstract

The properties of the human Y chromosome – namely, male specificity, haploidy and escape from crossing over — make it an unusual component of the genome, and have led to its genetic variation becoming a key part of studies of human evolution, population history, genealogy, forensics and male medical genetics. Next-generation sequencing (NGS) technologies have driven recent progress in these areas. In particular, NGS has yielded direct estimates of mutation rates, and an unbiased and calibrated molecular phylogeny that has unprecedented detail. Moreover, the availability of direct-to-consumer NGS services is fuelling a rise of 'citizen scientists', whose interest in resequencing their own Y chromosomes is generating a wealth of new data.

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Figure 1: A calibrated Y-chromosome phylogeny.
Figure 2: A comparison of the demographic histories of women and men revealed by mitochondrial DNA and Y-chromosome analysis.
Figure 3: Loss of Y in blood samples and its medical consequences.

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Acknowledgements

C.T.-S. is supported by a grant from the Wellcome Trust (grant number 098051).

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Correspondence to Mark A. Jobling or Chris Tyler-Smith.

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Glossary

Haploid

The state of having one chromosome copy per cell.

Short tandem repeats

(STRs). DNA sequences that contain a number (usually ≤50) of tandemly repeated short (2–6 bp) sequences, such as (GATA)n. The sequences are often polymorphic and are also known as microsatellites.

Haplogroups

Related sets of Y chromosomes that are collectively defined by specific, slowly mutating binary polymorphisms (usually single-nucleotide polymorphisms).

Phylogeny

A tree-like diagram that represents the evolutionary relationships among a set of sequences.

Maximum parsimony

A method for selecting the best evolutionary tree from a set of alternatives on the basis of which contains the fewest mutational changes.

Ascertainment bias

Bias in a dataset caused by the way that DNA sequence variants are identified or samples are collected.

Phylogeography

The analysis of the geographical distributions of different clades within a phylogeny, such as haplogroups in the Y-chromosome phylogeny.

Heterochromatin

A highly condensed, transcriptionally inert segment of the genome that is often composed of repeated DNA sequences. On the Y chromosome, heterochromatin is found mainly near the centromere and in the distal half of the long arm.

Euchromatin

The part of the genome that is in an extended conformation and contains transcriptionally active DNA.

Callable

Describes a DNA sequence in which reliable genotype calls can be made in next-generation sequencing because of the unambiguous mapping of reads to the reference sequence.

Gametologues

Similar sequences on the X and Y chromosomes that share an origin in the ancestral autosomal pair from which the current X and Y chromosomes have evolved.

Gene conversion

A nonreciprocal exchange of sequence information between one DNA molecule and another. Non-allelic gene conversion is active between repeated sequences on the Y chromosome.

Minisatellites

DNA sequences that contain a variable number (from ~10 to >1,000) of tandemly arranged repeat units that are each typically 10–100 bp in length.

Hotspots

Short regions of the genome (a few kilobases in length) in which meiotic crossing over is significantly increased above the genome average.

Resequencing

Taking a particular known sequence from an existing source, or an entire genome, and determining the equivalent sequence in several different individuals as a means by which to discover sequence variation.

Outgroup

A lineage or species that is more distantly related to a group of lineages or species than any of them is to each other.

Admixture

The mixing of distinct parental populations resulting in a new hybrid population.

Mitochondrial DNA

(mtDNA). The circular, maternally inherited genome carried by the mitochondrion, which is a cellular organelle.

Genetic drift

The random fluctuation of allele frequencies in a population due to chance variations in the contribution of each individual to the next generation.

Deep-rooting

Describes a human pedigree that contains the descendants of common ancestors who lived several or many generations ago.

Bayesian skyline plots

(BSPs). Plots of effective population size against time that summarize the demographic history of a population.

Neutral

In the context of this Review, describes genetic variation that has no effect on selective fitness.

Sertoli cell

Cells that are located in the walls of the seminiferous tubules of the testis and that act to support the development of sperm.

Induced pluripotent stem cells

Stem cells that can be directly generated from adult cells and differentiated into many cell types.

Genome-wide association studies

(GWAS). Studies of many common genome-wide variants (usually single-nucleotide polymorphisms) in different individuals that determine if any variant is associated with a particular trait.

Pseudoautosomal

Describes the behaviour of two regions of the sex chromosomes that display inheritance from both parents owing to crossing over between the X and Y chromosomes during male meiosis.

Population stratification

Systematic differences in allele frequencies between subgroups within a population.

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Jobling, M., Tyler-Smith, C. Human Y-chromosome variation in the genome-sequencing era. Nat Rev Genet 18, 485–497 (2017). https://doi.org/10.1038/nrg.2017.36

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