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. 2012 Dec;34(12):1035-44.
doi: 10.1002/bies.201200066. Epub 2012 Oct 10.

Sequencing of rhesus macaque Y chromosome clarifies origins and evolution of the DAZ (Deleted in AZoospermia) genes

Jennifer F Hughes  1 , Helen Skaletsky, David C Page
Affiliations

Sequencing of rhesus macaque Y chromosome clarifies origins and evolution of the DAZ (Deleted in AZoospermia) genes

Jennifer F Hughes et al. Bioessays. 2012 Dec.

Abstract

Studies of Y chromosome evolution often emphasize gene loss, but this loss has been counterbalanced by addition of new genes. The DAZ genes, which are critical to human spermatogenesis, were acquired by the Y chromosome in the ancestor of Old World monkeys and apes. We and our colleagues recently sequenced the rhesus macaque Y chromosome, and comparison of this sequence to human and chimpanzee enables us to reconstruct much of the evolutionary history of DAZ. We report that DAZ arrived on the Y chromosome about 38 million years ago via the transposition of at least 1.1 megabases of autosomal DNA. This transposition also brought five additional genes to the Y chromosome, but all five genes were subsequently lost through mutation or deletion. As the only surviving gene, DAZ experienced extensive restructuring, including intragenic amplification and gene duplication, and has been the target of positive selection in the chimpanzee lineage. Editor's suggested further reading in BioEssays Should Y stay or should Y go: The evolution of non-recombining sex chromosomes Abstract.

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Figures

Figure 1
Figure 1
Remnants of chromosome 3 transposition on rhesus and human MSYs. A: Dot-plot analyses of entire human (left) and rhesus (right) MSY sequences vs. 1.1-Mb region from human chromosome 3. Schematic representations of rhesus and human Y chromosomes are shown to scale. B: Separate dot-plot analyses of selected regions of human (left) and rhesus (right) MSY sequences vs. 1.1-Mb region from human chromosome 3. Position and orientation of Y chromosome DAZ genes and six chromosome 3 genes (including DAZL) are indicated by arrows on plot axes. For all plots, chromosome 3 sequence was masked with RepeatMasker (www.repeatmasker.org) prior to analysis. Each dot within the plot represents 100% identity within 30-bp window (A) or 20-bp window (B). Dot-plots were generated using custom perl code (“Fast Dot Plot” available at http://pagelab.wi.mit.edu/material-request.html). Abbreviations: MSY, male-specific Y; cen, centromere.
Figure 2
Figure 2
Structure of members of the DAZ gene family in human and rhesus macaque. A: The exon-intron structure of each member of the DAZ gene family is shown to scale. Vertical lines and boxes represent exons, and exon number is indicated below. Horizontal lines represent introns. Exons that are spliced into mRNA product are shown in blue, and exons that are in genomic sequence but not spliced into mRNA are shown in orange. Asterisk after exon number indicates presence of mutation disrupting dinucleotide splice site; absence of asterisk indicates intact dinucleotide splice site. Asterisk above exon 8 indicates shortened exon. Splicing patterns for human [7,8] and rhesus [5] genes determined by cDNA sequencing. B: Donor splice site strength of various versions of exon 8 was evaluated using maximum entropy analysis [39] of 9-mers at 5' splice sites. Scores for amplified copies of exon 8 in rhesus DAZ1 and DAZ2 are shown. Score for human DAZL is shown at left. Bars in graph are color-coded to indicate inclusion or exclusion in mRNA splicing as shown.
Figure 3
Figure 3
Phylogenetic analyses of DAZ gene family members in primates and evidence for positive selection in chimpanzee. A–C: Maximum likelihood trees based on aligned sequences from (A) mRNAs, (B) introns, and (C) exons 2–6. Sequences were aligned using ClustalW and adjusted by hand in MacVector 12.0. Phylogenetic trees were generated using DNAML in Phylip 3.69 [48] with default parameters (http://cmgm.stanford.edu/phylip/dnaml.html). Graphical representations of trees were generated using FigTree 1.3.1 (http://tree.bio.ed.ac.uk/software/figtree). Numerical identifiers in DAZ gene names differentiate copy number only and do not indicate interspecies orthologies. Scale for branch lengths given in substitutions per site. C: For genes with multiple RRM repeats, repeat number is indicated after dash. Lineage-specific dN/dS ratios were calculated using the free-ratio model implemented in PAML [46]. All non-zero dN/dS ratios are indicated on branches. To determine statistical significance, the log-likelihood ratio test was used to compare observed ratio to a neutral evolution model where dN/dS is fixed at 1 (model 1 vs. 2 in PAML) [47].
Figure 4
Figure 4
Degree of conservation of DAZ genomic sequences within species and between species. A–C: Dot-plot analyses of (A) rhesus DAZ1 vs. rhesus DAZ2, (B) rhesus DAZ1 vs. human DAZ1 and DAZ2 (in human MSY palindrome P2) and (C) human DAZ1 and DAZ2 (palindrome P2) vs. human DAZ3 and DAZ4 (palindrome P1). Each dot within the plot is color-coded to reflect window size as indicated. Position, orientation, and exon-intron structure of genes are shown schematically on each axis. Gray shading indicates location of conserved 30-kb upstream region in rhesus, which is largely absent in human. D: Sliding-window analyses for DAZ genomic sequences in rhesus. Pairwise percent identity was calculated in 1000-bp windows and displayed using VISTA [49].
Figure 5
Figure 5
Evolutionary history of the DAZ gene family. Phylogenetic tree shows evolutionary relationships between human, chimpanzee, and rhesus. Timeline is shown at left. Species divergence dates from http://www.timetree.org [25]. Dates of chromosome 3 transposition and initial DAZ duplication estimated as described in text. Timing of all other depicted events is only relative to other events. DAZ genes are shown as rectangles, with shading indicating major repeat domains. Palindromes shown as oppositely-facing block arrows. Abbreviations: MYA, millions of years ago; OWM, Old World monkey; NWM, New World monkey.
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