Short H2A histones, part I: parental conflict at the evolutionary scale

From the Malik and Henikoff labs (Basic Sciences)

Parenting is tough. From its first breath, a child demands an unending series of decisions, some small – what should they have for breakfast? Should I let them stay up late tonight? – some agonizing – how should I discipline them? How do I keep them safe? With so many questions of such potential consequence to the child’s ultimate success and happiness, it’s only natural that conflict will invariably arise between parents with differing points of views. So innate is this conflict, in fact, that it manifests not only in the behaviors and decisions of couples. Sometimes, it is embedded in our very DNA, playing out on an evolutionary scale, its resolution key to the fitness of our species. In a new study, published in PLOS Biology, the lab of Dr. Harmit Malik from the Basic Sciences Division at Fred Hutch, led by postdoctoral fellow Dr. Antoine Molaro, in collaboration with the lab of Dr. Steve Henikoff, identify a gene at the center of a genetic conflict between mother and father with implications for the fitness of their offspring.

This evolutionary tale begins in an unexpected place. The histone. An ancient structure with an essential role in every eukaryotic cell – to wrap the long strands of our DNA into stable, neatly organized bundles. The genes that encode the building blocks of this structure should be extremely evolutionary stable, lest any change disrupt their long-established and critical functions. But one small group of unconventional histone genes, called the short H2A histone genes, are evolving rapidly in placental mammals, raising the question of what roles they play in histone function and mammalian development, and what is driving their continued evolution. Working with a new mouse model lacking one of these genes – H2A.B – the researchers examined these questions with intriguing results.

H2A.B is predominantly expressed in developing sperm. To examine how it affects histone function, the authors examined chromatin structure in the sperm of H2A.B mutant mice. They found widespread loosening, or partial unwrapping, of the DNA around histones in these mutant mice, suggesting a key role for H2A.B in how histones wrap DNA. Surprisingly, though, this mutation had no effect on the formation or the function of sperm. What, then, was the purpose of expressing H2A.B in the sperm? Interestingly, although the mutant sperm had no trouble fertilizing eggs, the resulting embryos often died, and those that survived were significantly smaller than their wild-type counterparts. This finding is a classic example of a parental-effect gene, in which a mutation in a parent causes a phenotype in its child, even if the child does not itself have that mutation. Thus, the authors propose that H2A.B’s regulation of histone wrapping in the sperm is important for the development of the future embryo, likely by regulating the transmission of epigenetic information from parent to child.

H2A.B was not believed to be expressed in female mice. Nevertheless, the authors fortuitously decided to examine whether a mutation in the mother also impacted the embryo’s development. And, unexpectedly, they found that mothers containing a mutant H2A.B gene also produced smaller fetuses, irrespective of the genotype of the fetus itself. The authors therefore concluded that H2A.B. is a “biparental-effect gene”, in which its status in both mother and father impacts the growth of the embryo that results from their union, with the status of the gene in the embryo playing no role at all. Until, that is, it goes on to have children of its own.

The finding of a biparental growth effect not only offered an intriguing explanation as to what role H2A.B plays in development, but also gave the authors a key insight into the authors’ second question: why is this gene evolving so rapidly? The group believes that the H2A.B gene mediates a phenomenon known as parental antagonism, which, as they describe it, is “when alleles have different fitness effects on progeny depending on whether they are inherited maternally or paternally.” In this case, for instance, mom and dad may differ regarding optimal pup weight or litter size (mom is, after all, the only one of the two who has to nurture and birth said pups). H2A.B may therefore act to delicately balance these conflicting optima, and therefore  a mutation in this gene could shift this balance, proving both evolutionarily good (from the perspective of one parent) and bad (from the perspective of the other), and ultimately placing an imperative on the gene to accumulate additional mutations that shift it back in the other direction. Such a mutational dance would lead to a continuous, see-sawing evolution for this gene caught in the middle of a long-simmering parental conflict. This process, while complicated, offers an intriguing glimpse at the convoluted and sometimes conflicted incentives driving the evolutionary process. “Beginning to solve such an evolutionary conundrum…is quite satisfying”, said Dr. Molaro.

Although it is still unclear exactly why sperm require the unique DNA-wrapping properties of short H2A histones, their evolution has clearly had a lasting and likely positive impact on the development of placental mammals. But the existence of genes with the power to disrupt the normal workings of histones is not without its risks. For a story on the dangerous consequences of accidentally misusing this power, check out the other article in this month’s 2-part series on short H2A genes in development and disease, about the role these genes play in cancer.

H2A.B histones “imprinting” function in the developing sperm (paternal, blue) and egg (maternal, pink) exhibit conflicting parental effects on the developing embryo. Image provided by Dr. Antoine Molaro.

This work was supported by the Damon Runyon Cancer Research Foundation, the National Institutes of Health, and the Howard Hughes Medical Institute.

Fred Hutch/UW Cancer Consortium members Harmit Malik and Steven Henikoff contributed to this work

Molaro A, Wood AJ, Janssens D, Kindelay SM, Eickbush MT, Wu S, Singh P, Muller CH, Henikoff S, Malik HS. (2020) Biparental contributions of the H2A.B histone variant control embryonic development in mice. PLoS Biology 18(12): e3001001.