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Refined X Chromosome Assembly Hints at Possible Role in Sperm Production

NEW YORK (GenomeWeb News) – A US and UK team that delved into previously untapped stretches of sequence on the mammalian X chromosome has uncovered clues that sequences on the female sex chromosome may play a previously unappreciated role in sperm production.

The work, published online yesterday in Nature Genetics, also indicated such portions of the X chromosome may be prone to genetic changes that are more rapid than those described over other, better-characterized X chromosome sequences.

"We view this as the double life of the X chromosome," senior author David Page, director of the Whitehead Institute, said in a statement.

"[T]he story of the X has been the story of X-linked recessive diseases, such as color blindness, hemophilia, and Duchenne's muscular dystrophy," he said. "But there's another side to the X, a side that is rapidly evolving and seems to be attuned to the reproductive needs of males."

As part of a mouse and human X chromosome comparison intended to assess the sex chromosome's similarities across placental mammals, Page and his colleagues used a technique called single-haplotype iterative mapping and sequencing, or SHIMS, to scrutinize human X chromosome sequence and structure in more detail than was available previously.

With the refined human X chromosome assembly and existing mouse data, the team did see cross-mammal conservation for many X-linked genes, particularly those present in single copies. But that was not the case for a few hundred species-specific genes, many of which fell in segmentally duplicated, or "ampliconic," parts of the X chromosome. Moreover, those genes were prone to expression by germ cells in male testes tissue, pointing to a potential role in sperm production-related processes.

"X-ampliconic genes are expressed predominantly in testicular germ cells," the study authors noted, "and many were independently acquired since divergence from the common ancestor of humans and mice, specializing portions of their X chromosomes for sperm production."

The work was part of a larger effort to look at a theory known as Ohno's law, which predicts extensive X-linked gene similarities from one placental mammal to the next, Page and company turned to the same SHIMS method they used to get a more comprehensive view of the Y chromosome for previous studies.

Using that sequencing method, the group resequenced portions of the human X chromosome, originally assembled from a mishmash of sequence from the 16 or more individuals whose DNA was used to sequence the human X chromosome reference.

Their goal: to track down sections of segmental duplication, called ampliconic regions, that may have been missed or assembled incorrectly in the mosaic human X chromosome sequence.

"Ampliconic regions assembled from multiple haplotypes may have expansions, contractions, or inversions that do not accurately reflect the structure of any extant haplotype," the study's authors explained.

"To thoroughly test Ohno's law," they wrote, "we constructed a more accurate assembly of the human X chromosome's ampliconic regions to compare the gene contents of the human and mouse X chromosomes."

The team focused their attention on 29 predicted ampliconic regions of the human X chromosome, using SHIMS to generate millions of bases of non-overlapping X chromosome sequence.

With that sequence in hand, they went on to refine the human X chromosome assembly before comparing it with the reference sequence for the mouse X chromosome, which already represented just one mouse haplotype.

The analysis indicated that 144 of the genes on the human X chromosome don't have orthologs in mice, while 197 X-linked mouse genes lack human orthologs.

A minority of those species-specific genes arose as the result of gene duplication or gene loss events since the human and mouse lineages split from one around 80 million years ago, researchers determined. But most appear to have resulted from retrotransposition or transposition events involving sequences from autosomal chromosomes.

And when the team used RNA sequencing and existing gene expression data to look at which mouse and human tissues flip on particular genes, it found that many of the species-specific genes on the X chromosome showed preferential expression in testicular cells known for their role in sperm production.

Based on such findings, the study's authors concluded that "the gene repertoires of the human and mouse X chromosomes are products of two complementary evolutionary processes: conservation of single-copy genes that serve in functions shared by the sexes and ongoing gene acquisition, usually involving the formation of amplicons, which leads to the differentiation and specialization of X chromosomes for functions in male gametogenesis."

The group plans to incorporate results of its SHIMS-based assembly into the X chromosome portion of the human reference genome.

"This is a collection of genes that has largely eluded medical geneticists," the study's first author Jacob Mueller, a post-doctoral researcher in Page's Whitehead lab, said in a statement. "Now that we're confident of the assembly and gene content of these highly repetitive regions on the X chromosome, we can start to dissect their biological significance."

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