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African Turquoise Killifish Genome Gives Glimpse into Aging, Sex Chromosome Development

NEW YORK (GenomeWeb) — Two independent teams of researchers have sequenced the genome of the African turquoise killifish, a short-lived fish that has been proffered as a model of aging.

As the teams reported in separate Cell papers today, aging-related genes appear to cluster in the Nothobranchius fureri genome, and many of these genes seem to be under positive selection. In addition, as the Stanford University-led team noted, these clusters are located on the sex chromosomes, suggesting that the fish's short lifespan may have evolved in conjunction with its sex chromosomes. And the team led by the Leibniz Institute on Aging-Fritz Lipmann Institute has uncovered intra-species Y-chromosome polymorphisms that seem to reflect features of early XY chromosome evolution.

"The range of lifespans seen in nature is truly astonishing, and really we have very little insight into how this has evolved or how this works," said Anne Brunet, a professor of genetics at Stanford University and senior author of one of the studies, in a statement. "By having the genome of this fish and comparing it to other species, we start seeing differences that could underlie lifespan differences both between species and also within a species."

Brunet and her team have suggested that the African turquoise killifish might serve as a model organism for aging research. It lives for between four and six months, with variation between strains, but shares a number of characteristics with human aging — such as telomere loss, mitochondrial dysfunction, and cellular senescence, among others — despite its compressed lifespan.

Both teams sequenced and assembled the N. fureri genome using the inbred Zimbabwe-derived GRZ strain, with the Stanford team obtaining a 1.02 gigabase genome assembly and the Leibniz team obtaining a 1.24 gigabase genome assembly. They uncovered 28,494 and 26,141 protein-coding genes, respectively, as well as a number of RNA genes.

Aging-related genes, both teams noted, appeared to cluster together.

By comparing old and young MZM strain fish — which generally live longer than GRZ fish — and mid-life GRZ and MZM fish, Leibniz's Matthias Platzer and his colleagues uncovered differentially expressed aging-related genes.

Of the 10 positional gene enrichment regions they uncovered, they noted that two overlapped in a non-random manner and that one of those two was linked to wound response. As these two genes are downregulated in aging, the researchers suggested that they are co-regulated and their effect could be related to the decreased regeneration observed in aging.

They further noted a number of aging-related genes are under positive selection in N. fureri. One such gene that Platzer and his colleagues identified is id3, which is involved in TGF-β signaling and is upregulated during aging in both the brain and skin. Another is ikbip, a pro-apoptotic gene that is downregulated in skin aging.

Meanwhile, Brunet and her colleagues also homed on in a set of nearly 500 genes under positive selection in the turquoise killifish, including some 22 known aging-related genes such as the insulin receptor A gene and the IGF1 receptor gene.

Platzer and his colleagues also reported an overlap between the genes expressed during aging and those expressed during diapause, the state of suspended animation the fish enters when their ponds dry up. And Brunet and her colleagues further reported that aging-related genes involved in the insulin-IGF1-FOXO pathway that are involved in diapause in other species are under positive selection in killifish. This suggested to Brunet and her colleagues that — depending on the circumstances — genes in that pathway that are under positive selection might have a role in both diapause and the killifish's compressed lifespan.

Brunet and her colleagues also traced this clustering of aging-related genes to the nascent killifish sex chromosomes. The lifespan QTL and the sex-determining region are within the same linkage group, they said, located some 36 centimorgans to 38 centimorgans apart.

As the region is enriched for known aging and longevity genes, the researchers also suggested that a haplotype block, rather that a single gene, might be behind the lifespan differences seen in killifish. In addition, sex-determining regions usually are areas of suppressed recombination, a trait they too see in this region.

Though this could be a coincidence, the researchers noted that this close connection suggests the turquoise killifish might have evolved to couple strategies of fast reproduction with genes involved in overall fitness.

The killifish sex chromosomes, the Platzer-led team reported, exhibit intra-species variation. They traced male SNVs to a region of sg05, near known sex-linked markers. They noted that even though the male-specific region of the Y chromosome differed in size between the strains of the fish, the position of this peak of variation remained the same. The sg05 region, they added, was a prominent region of suppressed recombination.

Comparative analyses, Platzer and his colleagues said, suggest a two-step process leading to the development of the Y chromosome. First, an ancient event likely led to suppressed recombination in a 196-kilobase region, and that was then followed by the emergence or fixation of a sex-determining signal.

This secondary event appeared to have occurred independently in the different killifish strains, the researchers added, suggesting that these polymorphisms may reflect different stages of sex chromosome evolution. This, they noted, may enable studies of XY evolution "in action."

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