In biology, a species is defined as a group of organisms where two individuals are capable of reproducing fertile offspring, typically using sexual reproduction. Within similar species, horses and donkeys for example, the mismatch in number of chromosomes between each animal means the two cannot breed successfully with each other — or the resulting living offspring will be infertile, as is the mule.

"To understand speciation is to understand how these reproductive barriers evolved," says Nitin Phadnis PhD, Assistant Professor of Biology at the University of Utah and principal investigator for the research. "You call them new species when there are barriers that prevent them from breeding with each other. Identifying genes and uncovering the molecular basis of hybrid sterility or death, is key to understanding how new species evolve and remains one of the big and longstanding questions in biology since Darwin." Phadnis says new species evolve when two populations of one species become separated - usually geographically - and then "something changes in their genome..." 

His University of Utah study has identified a long-sought after "hybrid inviability gene" responsible for dead or infertile offspring when two species of fruit flies mate with each other. The discovery sheds light on genetic and molecular processes leading to formation of a new species. It may even provide clues to how cancers develop.

"We knew for decades that something like this gene ought to exist, and our approach finally allowed us to identify it."

Nitin Phadnis PhD, Assistant Professor of Biology, University of Utah, Principal Investigator and principal author of the research.

The research is published in the journal Science.

A big surprise is that the gene that makes fruit fly hybrids unable  to survive — named gfzf — is a "cell cycle-regulation gene" or "cell cycle-checkpoint gene". Gfzf normally is involved in stopping cell division and replication when defects are detected. But in the University of Utah study, when mutated and disabled, gfzf allowed for survival of male hybrids of both fruit fly species.

The gfzf gene evolved quickly, which is expected in hybrid inviability genes. But is also a surprise as cell cycle-checkpoint genes usually evolve slowly being "conserved" genes. Conserved genes are maintained throughout evolution as they are essential to the existence of most organisms, and therefore can be found across most species.

"Cancer biologists are interested in cell cycle checkpoints because you can get cancer when those go bad — allowing cells to proliferate uncontrolled. Biologists want to understand this machinery. Our work shows some of the components in cell cycle policing machinery may also be quickly changing."

Nitin Phadnis PhD

Both Drosophila Melanogaster and Drosophila Simulans, have been around for a couple of million years. Geneticists have studied them ever since 1910, when they first recognized hybrids from matings between the two species died. Over the past decade, scientists have identified two other genes implicated in death and infertility of offspring. In D. Simulans, a gene named Lhr (for lethal hybrid rescue) and in the D. Melanogaster, a gene named Hmr (for hybrid male rescue). However, if either of these genes is missing — hybrid male offspring do survive. But, evidence also exists that a third, unknown gene, may also be required.

Breeding mutant male hybrid fruit flies that live

The Phadnis group mated mutant Drosophila Simulans males with normal Drosophila Melanogaster females, to determine which mutated genes allowed some male hybrids to live. The resulting offspring included 300,000 sterile  hybrid females — and only 32 living males, also sterile.

Only six of these males were alive due to a mutation that disabled the yet-unidentified hybrid inviability gene.

Researchers then sequenced the genomes of those six male hybrid fruit flies, and of both strains of parent fruit flies. Comparing the genomes of the six to the genomes of both sets of parents, they identified 600 to 1,200 new mutations in each of the six males. In what Phadnis calls "a surprisingly clean result," they found only a single Drosophila simulans fruit fly gene mutated in all six live hybrid males, on the third chromosome named gfzf.

The gfzf gene from Drosophila Simulans is the hybrid inviability gene which normally kills hybrid males but allows them to live if silenced by a mutation.

Researchers don't yet know what gfzf gene's normal role is at a molecular level, but Phadnis plans to find out. He also wants to know whether more genes are involved in inviable offspring from mating the two fruit flies. Why would a gene make hybrids inviable or incapable of surviving? And why doesn't natural selection eliminate it over time? Phadnis believes such genes are selected for some characteristic yet unidentified —"the hybrid's death is an accidental consequence of that evolution."

Phadnis speculates gfzf may be favored by natural selection because it helps control so-called jumping genes, which can disrupt essential genes to create disease-causing mutations. A jumping gene is a transposable element (TE) or a DNA sequence that can change its position within the genome. This sometimes creates or reverses mutations and alters the cell's genome size. Barbara McClintock discovered jumping genes, earning her a Nobel prize in 1983.

Abstract
Speciation, the process by which new biological species arise, involves the evolution of reproductive barriers, such as hybrid sterility or inviability between populations. However, identifying hybrid incompatibility genes remains a key obstacle in understanding the molecular basis of reproductive isolation. We devised a genomic screen, which identified a cell cycle–regulation gene as the cause of male inviability in hybrids resulting from a cross between Drosophila melanogaster and D. simulans. Ablation of the D. simulans allele of this gene is sufficient to rescue the adult viability of hybrid males. This dominantly acting cell cycle regulator causes mitotic arrest and, thereby, inviability of male hybrid larvae. Our genomic method provides a facile means to accelerate the identification of hybrid incompatibility genes in other model and nonmodel systems.

Co-authors and funders
Phadnis conducted the study with University of Utah postdoctoral fellow Kimberly Frizzell and doctoral student Jacob Cooper; technicians Emily Baker and Aida de la Cruz, of the Fred Hutchinson Cancer Research Center in Seattle; and professors Jay Shendure and Harmit Malik, genetics doctoral student Jacob Kitzman and undergraduate Emily Hsieh of the University of Washington. Kitzman now is a professor at University of Michigan. Phadnis began the study as a postdoctoral fellow in Malik's laboratory, and then completed it during the last two years at Utah.

The research was funded by the Howard Hughes Medical Institute, Life Sciences Research Foundation, National Institutes of Health, National Science Foundation, Mathers Foundation and Phadnis' Mario R. Capecchi Endowed Chair in Biology from the George S. and Dolores Doré Eccles Foundation.

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Jan 29, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   

Drosophila Melanogaster cannot mate successfully with Drosophila Simulans.
Their offspring die or are infertile. New research identified the gfzf gene as the
"hybrid inviability gene" responsible. gfzf may help control jumping genes.
Image Credit: Public Domain