Dynamics of a human interparalog gene conversion hotspot - PubMed (original) (raw)

Comparative Study

Dynamics of a human interparalog gene conversion hotspot

Elena Bosch et al. Genome Res. 2004 May.

Abstract

Gene conversion between paralogs can alter their patterns of sequence identity, thus obscuring their evolutionary relationships and affecting their propensity to sponsor genomic rearrangements. The details of this important process are poorly understood in the human genome because allelic diversity complicates the interpretation of interparalog sequence differences. Here we exploit the haploid nature of the Y chromosome, which obviates complicating interallelic processes, together with its known phylogeny, to understand the dynamics of conversion between two directly repeated HERVs flanking the 780-kb AZFa region on Yq. Sequence analysis of a 787-bp segment of each of the HERVs in 36 Y chromosomes revealed one of the highest nucleotide diversities in the human genome, as well as evidence of a complex patchwork of highly directional gene conversion events. The rate of proximal-to-distal conversion events was estimated as 2.4 x 10(-4) to 1.2 x 10(-3) per generation (3.9 x 10(-7) to 1.9 x 10(-6) per base per generation), and the distal-to-proximal rate as about one-twentieth of this. Minimum observed conversion tract lengths ranged from 1 to 158 bp and maximum lengths from 19 to 1365 bp, with an estimated mean of 31 bp. Analysis of great ape homologs shows that conversion in this hotspot has a deep evolutionary history.

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Figures

Figure 1

Figure 1

HERV structures, HERV-sponsored rearrangements, and the phylogenetic positions of known double-crossover and gene conversion events. (A) Structures of the proximal and distal AZFa HERVs, showing blocks of identity >200 bp (hatched boxes) and the L1 fragment insertion in the distal HERV. Identity blocks A through D are named according to Bosch and Jobling (2003). Flanking specific primers (large arrows) and primers used for the amplification of the region between identity blocks A and D (small arrows) are shown. (B) Possible sequence rearrangements sponsored by the HERVs: Single meiotic crossover between misaligned sister chromatids (in the same orientation) causes deletion or duplication of the AZFa region, both of which have been observed; double crossover causes the transfer of a large segment of one HERV to the other, observed in the proximal-to-distal case only; and gene conversion causes the nonreciprocal transfer of small segments, observed in both polarities. (C) Phylogeny of the Y chromosome showing known double-crossover and gene conversion events. Two examples of proximal-to-distal transfer through double-crossover are known: The concomitant loss of the L1 segment from the distal HERV is typed as a binary marker (Casanova et al. 1985) and defines haplogroup J (12f2.1). The second occurrence (12f2.2) is phylogenetically equivalent to binary markers defining haplogroup D2 (Blanco et al. 2000). A distal-to-proximal conversion of between 36 and 72 bp is phylogenetically equivalent to the marker P25, defining haplogroup R1b; one example of a chromosome with a proximal-to-distal conversion within this haplogroup is also known (Bosch and Jobling 2003).

Figure 2

Figure 2

Sequence states of the 24 PSVs in proximal and distal inter-AD segments within 36 Y chromosomes, organized according to the Y phylogeny. Bases shown in white on black are distal specific, and those in black on white are proximal specific, as defined by the reference sequence (Ref). Names of DNA samples are given on the right; on the left, a simplified version of the Y phylogeny (Y Chromosome Consortium 2002) shows the phylogenetic relationships and haplogroup names of the chromosomes analyzed. Sequences within haplogroup J contain a deletion of 13 bp between PSVs 18 and 19, in both proximal and distal sequences. Case 1, case 2, and YCC26 proximal and distal sequences have been reported previously (respectively, AJ511660-1, AJ511663-4, AJ511666-7; Bosch and Jobling 2003). Sequence positions from 103 to 724 (bottom) give coordinates within the inter-AD segments: The position labeled 103 is equivalent to nucleotide no. 11739 on the plus strand of AC002992 for the proximal HERV, and to nucleotide no. 144340 on the minus strand of AC005820 for the distal HERV.

Figure 3

Figure 3

Number of independent proximal-to-distal conversion events within the sample. Sequence states of the PSVs within the distal inter-AD segment are shown schematically as small filled or empty circles and are defined as proximal or distal specific according to the reference sequence; spacing is approximately to scale. Each horizontal line represents one independent event, as deduced from the sequences shown in Fig. 2. The phylogeny to the left shows the haplogroup within which each event occurred and, adjacent to branches, the estimated age in generations (and its range as ±SD) of each branch, taken from published dates (Hammer and Zegura 2002) and assuming a generation time of 25 years. Branches G and H are included, even though they contain no conversions, because their ages are required in the rate calculation. Branches D and J are omitted because their lack of PSVs makes them uninformative.

Figure 4

Figure 4

Phylogenetic network analysis and sequence comparison of human, chimp, and gorilla inter-AD segments. (A) Phylogenetic network showing the relationships between inter-AD segments in the three species, produced using SplitsTree. Hu indicates human; Ch, chimpanzee; Go, gorilla; Prox, proximal HERV; and Dist, distal HERV. (B) Sequence states of all variant positions in the three species are shown. Human PSVs are indicated by triangles. Sequence numbering is as in Fig. 2, up to position 507. Beyond this point, one base is added to each number to take account of the gap introduced into the human sequence to facilitate sequence alignments.

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WEB SITE REFERENCES

    1. http://www-ab.informatik.uni-tuebingen.de/software/splits/welcome_en.html; SplitsTree software.

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