Genome dynamics and evolution

Our aim is to document the relative contributions of different mutation processes, and to understand the genetic and environmental factors that influence mutation rates, particularly processes that generate structural variation.

Genetic diseases can be caused by several types of variation in genomic DNA. We are investigating the functional impact of changes in DNA structure, ranging from single-base deletions to multi-megabase rearrangements, which are collectively known as Structural Variation (SV). A detailed understanding of human mutation processes will allow us to predict disease-causing mutations not yet seen clinically and will inform clinical decision-making, helping to distinguish benign and pathogenic variants and to identify the likely risk that a pathogenic mutation will be passed on to future generations. Our investigations are leading to a greater understanding of genetic diseases as well as shedding light on human populations, their evolution and their migrations.

[Matt Hurles, Wellcome Trust Sanger Institute]

Background

Diploid species can gain significant evolutionary advantages from cutting and splicing their homologous chromosomes each generation in a process known as 'homologous recombination' (HR). However, this process is inherently risky.

Simplified scheme of alternative resolution pathways (crossover or gene conversion) of an HR intermediate.

Simplified scheme of alternative resolution pathways (crossover or gene conversion) of an HR intermediate. [Matt Hurles, Wellcome Trust Sanger Institute]
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If chromosomes are spliced incorrectly, genes can be lost, gained or disrupted, resulting in diverse diseases known as 'genomic disorders'. Organisms manage this risk by carefully regulating the process of recombination and ensuring that only highly similar sequences are spliced together. As a consequence, programmed recombination between allelic sequences on homologous chromosomes only occurs once per generation, during the meiotic cell divisions that are limited to developing germ cells (sperm and ova). In addition to its programmed function in meiosis, HR also plays a fundamental role in the somatic cells of the body during the repair of damaging DNA lesions known as Double Strand Breaks (DSB). The focus of our research is to understand how HR generates a mutable genome, both in terms of the pathogenic consequences of imprecise HR, and the evolutionary implications of an ever-changing genome.

During the process of HR between two DNA duplexes, intermediate structures are formed that can be resolved in one of two ways. Either a crossover results - after which both products contain portions of the original duplexes, or a gene conversion results in which a limited amount of sequence information is carried from one duplex to the other, but not vice versa. In DSB repair, the gene conversion pathway is preferred over the crossover pathway; so as to minimise the chance of deleterious rearrangements. In meiotic recombination, both pathways are in operation.

Deletions, duplications, inversions and gene conversions.

Deletions, duplications, inversions and gene conversions. [Matt Hurles, Wellcome Trust Sanger Institute]
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Compared with other eukaryotic genomes, an appreciable portion of the human genome comprises long, highly-similar duplicated sequences known as 'segmental duplications'. It has been suggested that these segmental duplications have facilitated the development of novel gene functions in recent primate evolution. However, in contrast to their possible long-term benefits, the presence of segmental duplications renders the human genome susceptible to mistakes in HR. In rare meioses, these segmental duplications are mistaken for allelic sequences, with the result that chromosomes are incorrectly spliced. We know very little about the dynamics of this process, known as Non-Allelic Homologous Recombination (NAHR), but we do know that NAHR resulting in crossovers can result in disease-causing rearrangements such as deletions, for example male infertility, duplications, for example Charcot-Marie Tooth disease - a peripheral neuropathy, and inversions, for example Haemophilia. Similarly, NAHR resulting in gene conversion can generate pathogenic mutations by introducing non-functional mutations from a pseudogene into an expressed gene, for example Congenital adrenal hyperplasia.

Research

Mutation processes in the human genome.

Mutation processes in the human genome. [Matt Hurles, Wellcome Trust Sanger Institute]
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A fundamental mechanism of genome variation

NAHR (gene conversion and rearrangement) is one of only a limited number of mutational processes that generates genomic variation. Compared to processes such as base substitution or microsatellite expansion and contraction, very little is known about NAHR. We have little understanding of which locations within the genome are susceptible to NAHR, nor do we know much about what factors determine the rates of NAHR at specific loci or how they vary among individuals.

The gene conversions and rearrangements generated by NAHR need not be pathogenic, but contribute to sequence variation and structural polymorphism (for example the extensive polymorphism in copy number of Opsin and CYP2D6 genes that contribute to colour-blindness and adverse drug reactions respectively) in the human genome.

Strategies for interrogating NAHR.

Strategies for interrogating NAHR. [Matt Hurles, Wellcome Trust Sanger Institute]
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Our strategy for improving our understanding of genome dynamics

Our objective is to provide insights into fundamental pathogenic mechanisms and novel processes of evolutionary change by improving our understanding of interactions between duplicated sequences within the human genome. In the past, such investigations of mutational dynamics have taken one of two approaches:

  • Single Meioses - Identifying rare mutation events in a single generation, by analysing pedigrees, or by studying sperm DNA (in which each haploid genome represents an independent product of meiosis).
  • Many meioses - Analysing variation, either in a diverse population or between closely-related species, and using population genetic methods to infer features of the underlying evolutionary process from the products of cumulative mutational events.
Using PCR colonies to haplotype individual DNA molecules.

Using PCR colonies to haplotype individual DNA molecules. [Matt Hurles, Wellcome Trust Sanger Institute]

We are adopting both of these strategies for investigating NAHR. First, we are developing efficient single molecule PCR methods to detect chromosomal rearrangements and gene conversion events in pools of sperm genomes. We are using sensitive methods for discriminating between SNP alleles to identify rare recombinant haplotypes against a high background of non-recombined haplotypes. Second, we are resequencing a number of duplicated loci in diverse humans and higher primates to investigate sequence variation and haplotype diversity in and around segmental duplications. We are also developing population genetic methods and bioinformatics tools to facilitate these projects and to maximise the information gained from the ongoing chimpanzee genome project and HapMap project. In addition, we have a number of active collaborations in human population genetics.

Selected publications

  • Global variation in copy number in the human genome.

    Redon R, Ishikawa S, Fitch KR, Feuk L, Perry GH, Andrews TD, Fiegler H, Shapero MH, Carson AR, Chen W, Cho EK, Dallaire S, Freeman JL, González JR, Gratacòs M, Huang J, Kalaitzopoulos D, Komura D, MacDonald JR, Marshall CR, Mei R, Montgomery L, Nishimura K, Okamura K, Shen F, Somerville MJ, Tchinda J, Valsesia A, Woodwark C, Yang F, Zhang J, Zerjal T, Zhang J, Armengol L, Conrad DF, Estivill X, Tyler-Smith C, Carter NP, Aburatani H, Lee C, Jones KW, Scherer SW and Hurles ME

    Nature 2006;444;7118;444-54

    PUBMED: 17122850; DOI: 10.1038/nature05329; PMC: 2669898

  • A high-resolution survey of deletion polymorphism in the human genome.

    Conrad DF, Andrews TD, Carter NP, Hurles ME and Pritchard JK

    Nature genetics 2006;38;1;75-81

    PUBMED: 16327808; DOI: 10.1038/ng1697

  • A chromosomal rearrangement hotspot can be identified from population genetic variation and is coincident with a hotspot for allelic recombination.

    Lindsay SJ, Khajavi M, Lupski JR and Hurles ME

    American journal of human genetics 2006;79;5;890-902

    PUBMED: 17033965; DOI: 10.1086/508709; PMC: 1698570

  • Relative impact of nucleotide and copy number variation on gene expression phenotypes.

    Stranger BE, Forrest MS, Dunning M, Ingle CE, Beazley C, Thorne N, Redon R, Bird CP, de Grassi A, Lee C, Tyler-Smith C, Carter N, Scherer SW, Tavaré S, Deloukas P, Hurles ME and Dermitzakis ET

    Science (New York, N.Y.) 2007;315;5813;848-53

    PUBMED: 17289997; DOI: 10.1126/science.1136678; PMC: 2665772

  • Assaying chromosomal inversions by single-molecule haplotyping.

    Turner DJ, Shendure J, Porreca G, Church G, Green P, Tyler-Smith C and Hurles ME

    Nature methods 2006;3;6;439-45

    PUBMED: 16721377; DOI: 10.1038/nmeth881; PMC: 2690135

  • The dual origin of the Malagasy in Island Southeast Asia and East Africa: evidence from maternal and paternal lineages.

    Hurles ME, Sykes BC, Jobling MA and Forster P

    American journal of human genetics 2005;76;5;894-901

    PUBMED: 15793703; DOI: 10.1086/430051; PMC: 1199379

  • Native American Y chromosomes in Polynesia: the genetic impact of the Polynesian slave trade.

    Hurles ME, Maund E, Nicholson J, Bosch E, Renfrew C, Sykes BC and Jobling MA

    American journal of human genetics 2003;72;5;1282-7

    PUBMED: 12644966; DOI: 10.1086/374827; PMC: 1180280

  • Y chromosomal evidence for the origins of oceanic-speaking peoples.

    Hurles ME, Nicholson J, Bosch E, Renfrew C, Sykes BC and Jobling MA

    Genetics 2002;160;1;289-303

    PUBMED: 11805064; PMC: 1461928

  • Deciphering past human population movements in Oceania: provably optimal trees of 127 mtDNA genomes.

    Pierson MJ, Martinez-Arias R, Holland BR, Gemmell NJ, Hurles ME and Penny D

    Molecular biology and evolution 2006;23;10;1966-75

    PUBMED: 16855009; DOI: 10.1093/molbev/msl063; PMC: 2674580