Transmission distortion affecting human noncrossover but not crossover recombination: a hidden source of meiotic drive.

Meiotic recombination ensures the correct segregation of homologous chromosomes during gamete formation and contributes to DNA diversity through both large-scale reciprocal crossovers and very localised gene conversion events, also known as noncrossovers. Considerable progress has been made in understanding factors such as PRDM9 and SNP variants that influence the initiation of recombination at human hotspots but very little is known about factors acting downstream. To address this, we simultaneously analysed both types of recombinant molecule in sperm DNA at six highly active hotspots, and looked for disparity in the transmission of allelic variants indicative of any cis-acting influences.

The man behind the DNA fingerprints: an interview with Professor Sir Alec Jeffreys.

In this interview we talk with Professor Sir Alec Jeffreys about DNA fingerprinting, his wider scientific career, and the past, present and future of forensic DNA applications.The podcast with excerpts from this interview is available at: http://www.biomedcentral.

Human telomeres that carry an integrated copy of human herpesvirus 6 are often short and unstable, facilitating release of the viral genome from the chromosome.

Linear chromosomes are stabilized by telomeres, but the presence of short dysfunctional telomeres triggers cellular senescence in human somatic tissues, thus contributing to ageing. Approximately 1% of the population inherits a chromosomally integrated copy of human herpesvirus 6 (CI-HHV-6), but the consequences of integration for the virus and for the telomere with the insertion are unknown. Here we show that the telomere on the distal end of the integrated virus is frequently the shortest measured in somatic cells but not the germline.

Recombination regulator PRDM9 influences the instability of its own coding sequence in humans.

PRDM9 plays a key role in specifying meiotic recombination hotspot locations in humans and mice via recognition of hotspot sequence motifs by a variable tandem-repeat zinc finger domain in the protein. We now explore germ-line instability of this domain in humans. We show that repeat turnover is driven by mitotic and meiotic mutation pathways, the latter frequently resulting in substantial remodeling of zinc fingers.

A major recombination hotspot in the XqYq pseudoautosomal region gives new insight into processing of human gene conversion events.

Recombination plays a fundamental role in meiosis. Non-exchange gene conversion (non-crossover, NCO) may facilitate homologue pairing, while reciprocal crossover (CO) physically connects homologues so they orientate appropriately on the meiotic spindle. In males, X-Y homologous pairing and exchange occurs within the two pseudoautosomal regions (PARs) together comprising <5% of the human sex chromosomes.

Variants of the protein PRDM9 differentially regulate a set of human meiotic recombination hotspots highly active in African populations.

PRDM9 is a major specifier of human meiotic recombination hotspots, probably via binding of its zinc-finger repeat array to a DNA sequence motif associated with hotspots. However, our view of PRDM9 regulation, in terms of motifs defined and hotspots studied, has a strong bias toward the PRDM9 A variant particularly common in Europeans. We show that population diversity can reveal a second class of hotspots specifically activated by PRDM9 variants common in Africans but rare in Europeans.

L1 hybridization enrichment: a method for directly accessing de novo L1 insertions in the human germline.

Long interspersed nuclear element 1 (L1) retrotransposons are the only autonomously mobile human transposable elements. L1 retrotransposition has shaped our genome via insertional mutagenesis, sequence transduction, pseudogene formation, and ectopic recombination. However, L1 germline retrotransposition dynamics are poorly understood because de novo insertions occur very rarely: the frequency of disease-causing retrotransposon insertions suggests that one insertion event occurs in roughly 18-180 gametes.

PRDM9 variation strongly influences recombination hot-spot activity and meiotic instability in humans.

PRDM9 has recently been identified as a likely trans regulator of meiotic recombination hot spots in humans and mice. PRDM9 contains a zinc finger array that, in humans, can recognize a short sequence motif associated with hot spots, with binding to this motif possibly triggering hot-spot activity via chromatin remodeling. We now report that human genetic variation at the PRDM9 locus has a strong effect on sperm hot-spot activity, even at hot spots lacking the sequence motif.

Dynamics and processes of copy number instability in human gamma-globin genes.

Copy number variation in the human genome is prevalent but relatively little is known about the dynamics of DNA rearrangement. We therefore used the duplicated gamma-globin genes as a simple system to explore de novo copy number changes. Rearrangements that changed gene number were seen in both germline and somatic DNA, and mainly arose by unequal sister chromatid exchange between homologous sequences, with evidence from recurrent mosaic rearrangements that many, if not all, of these events in sperm arise before meiosis.

Analysis of meiotic recombination products from human sperm.

Traditional methods for surveying meiotic recombination in humans are limited to pedigree and linkage disequilibrium analyses. We have developed assays that allow the direct detection of crossover and gene conversion molecules in batches of sperm DNA. To date, we have characterized 26 recombination hotspots by allele-specific PCR and selectively amplified recombinant DNA molecules from these regions.

The rise and fall of a human recombination hot spot.

Human meiotic crossovers mainly cluster into narrow hot spots that profoundly influence patterns of haplotype diversity and that may also affect genome instability and sequence evolution. Hot spots also seem to be ephemeral, but processes of hot-spot activation and their subsequent evolutionary dynamics remain unknown. We now analyze the life cycle of a recombination hot spot.

Minisatellite MS32 alleles show population specificity among Thai, Chinese, and Japanese.

Lineages of structurally related alleles at minisatellite MS32 in human populations show considerable differentiation at the continental level. However, the regional specificity of these lineages remains unknown. We now describe the comparison of allele structures in Thai, Han Chinese, and Japanese populations with lineages previously established for North Europeans and Africans.

Processes of de novo duplication of human alpha-globin genes.

Ectopic recombination between repeated but nonallelic DNA sequences plays a major role in genome evolution, creating gene families and generating copy number variation and pathological rearrangements in human chromosomes. Previous studies on the alpha2- and alpha1-globin genes have shown that de novo deletions common in alpha(+)-thalassemics can be directly accessed in human DNA and provide an informative system for studying deletion dynamics and processes. However, nothing is known about the reciprocal products of ectopic recombination, namely gene duplications.

Species-wide distribution of highly polymorphic minisatellite markers suggests past and present genetic exchanges among house mouse subspecies.

Background: Four hypervariable minisatellite loci were scored on a panel of 116 individuals of various geographical origins representing a large part of the diversity present in house mouse subspecies. Internal structures of alleles were determined by minisatellite variant repeat mapping PCR to produce maps of intermingled patterns of variant repeats along the repeat array. To reconstruct the genealogy of these arrays of variable length, the specifically designed software MS_Align was used to estimate molecular divergences, graphically represented as neighbor-joining trees.

Processes of copy-number change in human DNA: the dynamics of {alpha}-globin gene deletion.

Ectopic recombination between locally repeated DNA sequences is of fundamental importance in the evolution of gene families, generating copy-number variation in human DNA and often leading to pathological rearrangements. Despite its importance, little is known about the dynamics and processes of these unequal crossovers and the degree to which meiotic recombination plays a role in instability. We address this issue by using as a highly informative system the duplicated alpha-globin genes in which ectopic recombination can lead to gene deletions, often very prevalent in populations affected by malaria, as well as reduplications.

Polymorphism in the activity of human crossover hotspots independent of local DNA sequence variation.

Meiotic crossovers in the human genome cluster into highly localized hotspots identifiable indirectly from patterns of DNA diversity and directly by high-resolution sperm typing. Little is known about factors that control hotspot activity and the apparently rapid turnover of hotspots during recent evolution. Clues can, however, be gained by characterizing variation in sperm crossover activity between men.

Seventh international meeting on single nucleotide polymorphism and complex genome analysis: 'ever bigger scans and an increasingly variable genome'.

In September 2005, the seventh international meeting on single nucleotide polymorphism (SNP) and complex genome analysis was held in Hinckley, near Leicester, UK and the meeting was organised by Anthony Brookes, Stephen Chanock, Ivo Gut, Alec Jeffreys and Pui-Yan Kwok. Similar to prior meetings, the 3-day meeting focused on new trends and methods in the analysis of SNPs and complex human disease. A substantial portion of the meeting was devoted to preliminary analyses of data emerging from the International HapMap Consortium and addressed key issues in patterns of recombination, linkage disequilibrium and population genetics.

Allelic recombination and de novo deletions in sperm in the human beta-globin gene region.

Meiotic recombination is of fundamental importance in creating haplotype diversity in the human genome and has the potential to cause genomic rearrangements by ectopic recombination between repeat sequences and through other changes triggered by recombination-initiating events. However, the relationship between allelic recombination and genome instability in the human germline remains unclear. We have therefore analysed recombination and DNA instability in the delta-, beta-globin gene region and its associated recombination hotspot.

Factors influencing recombination frequency and distribution in a human meiotic crossover hotspot.

Little is known about the factors that influence the frequency and distribution of meiotic recombination events within human crossover hotspots. We now describe the detailed analysis of sperm recombination in the NID1 hotspot. Like the neighbouring MS32 hotspot, the NID1 hotspot is associated with a minisatellite, suggesting that hotspots predispose DNA to tandem repetition.

Human tandem repeat sequences in forensic DNA typing.

It has been 20 years since the first development of DNA fingerprinting and the start of forensic DNA typing. Ever since, human tandem repeat DNA sequences have been the main targets for forensic DNA analysis. These repeat sequences are classified into minisatellites (or VNTRs) and microsatellites (or STRs).

Activation of the ALT pathway for telomere maintenance can affect other sequences in the human genome.

Immortal human cells maintain telomere length by the expression of telomerase or through the alternative lengthening of telomeres (ALT). The ALT mechanism involves a recombination-like process that allows the rapid elongation of shortened telomeres. However, it is not known whether activation of the ALT pathway affects other sequences in the genome.

Localized breakdown in linkage disequilibrium does not always predict sperm crossover hot spots in the human MHC class II region.

To investigate the relationship between meiotic crossover hot spots and block-like linkage disequilibrium (LD), we have extended our high-resolution studies of the human MHC class II region to a 90-kb segment upstream of the HLA-DOA gene. LD blocks in this region are not as well defined as in the neighboring 210-kb DNA segment but do show two regions of LD breakdown in which coalescent analysis indicates substantial historical recombination. Sperm crossover analysis of one region revealed a novel localized hot spot similar in intensity and morphology to most other MHC hot spots.

Human recombination hot spots hidden in regions of strong marker association.

The fine-scale distribution of meiotic recombination events in the human genome can be inferred from patterns of haplotype diversity in human populations but directly studied only by high-resolution sperm typing. Both approaches indicate that crossovers are heavily clustered into narrow recombination hot spots. But our direct understanding of hot-spot properties and distributions is largely limited to sperm typing in the major histocompatibility complex (MHC).