Inside AJHG: A Chat with Levi Teitz and David Page

Posted By: Sarah Ratzel, PhD, Science Editor, AJHG 

Each month, the editors of The American Journal of Human Genetics interview the author(s) of a recently published paper. This month, we check in with Levi Teitz and David Page to discuss their paper “Selection Has Countered High Mutability to Preserve the Ancestral Copy Number of Y Chromosome Amplicons in Diverse Human Lineages.”

20180820_LeviTietz-DavidPage
Levi Teitz, PhD, and David Page, MD (photo courtesy Dr. Page)

AJHG: What caused you to start working on this project? 

Levi: Our lab has a long history of studying the Y chromosome, but the ampliconic regions were always a bit of a mystery because of how difficult they are to study, due to their complex architecture and high sequence identity between copies. With the advent of high-throughput sequencing technologies and large, publicly available datasets, it seemed like a good time to revisit questions about amplicon variation and evolution with those new tools at our disposal.

David: The Y chromosome has been an enigma to geneticists for the last century, largely because it doesn’t play by the usual rules of being transmitted from both mother and father, and recombining with a homolog along its length, in meiosis. Despite being a sex chromosome, the Y chromosome is transmitted clonally – asexually – from father to son to son; it stands apart from all other nuclear chromosomes in this respect. This has led to all manner of unfounded insults regarding the Y chromosome’s character, medical relevance, and future prospects. My colleagues and I have spent decades defending the honor of the chromosome in the face of these insults.

AJHG: What about this paper most excites you? 

Levi: The new evolutionary questions it raises. The amplicons are extraordinarily divergent between species – so much so that it’s essentially impossible to reconstruct the steps that evolution took to get from the ancestral mammalian or primate amplicons to modern-day Y chromosomes. When we began this project, we expected that we could observe these evolutionary steps by looking within only humans. Instead, we found that the amplicon variation within human populations is an evolutionary dead end, and that the ancestral amplicon structure has been preserved for hundreds of thousands of years! This is a bit of a paradox: why is amplicon structure maintained in humans but so divergent between species? This is a hard problem, but solving it should provide incredible insight into amplicon evolution and function.

David: Learning something unanticipated about a subject you love is exciting. Massive palindromes and amplicons carrying spermatogenesis genes were known to dot the genomic landscape of the human Y chromosome, and they are frequently subject to deletion or rearrangement through non-allelic homologous recombination. The excitement for me here arises from both a computational advance and a biological insight. First, graduate student Levi Teitz, with guidance from Helen Skaletsky, mastered the computational challenge of robustly and accurately discerning the copy numbers of many different Y amplicons from whole-genome shotgun sequence data. Second, Levi applied these computational tools to the 1000 Genomes males, thereby characterizing Y amplicon copy number variation (CNV) around the globe. While the existence of such Y-amplicon CNV was unsurprising, the predominance of consistent patterns of Y-amplicon copy numbers around the globe (actually, across Y chromosome haplotypes) surprised me, and indicated that natural selection had optimized and consistently favored specific copy numbers for a host of Y amplicons. Natural selection, whose ability to maintain genes on the clonally transmitted Y had often been impugned, has evidently been effective at policing Y-amplicon copy numbers. Natural selection is alive and well on the human Y chromosome, even the parts where we might least expect it!

AJHG: Thinking about the bigger picture, what implications do you see from this work for the larger human genetics community?

Levi: Beyond improving our understanding of the Y chromosome, our work highlights the fact that the genome can change in unexpected ways. Much genomic research today focuses exclusively on the parts of the genome that are easiest to study: single-copy coding sequence. This paper demonstrates that not only does the rest of the genome have profound evolutionary and phenotypic effects, it also varies in ways that are exquisitely dependent on its repetitive structure. In fact, it would be impossible to understand the phenotypic and evolutionary stories without first understanding the underlying complex structure of these genomic regions. There are still parts of the human genome where complex structures are unresolved; who knows what we will discover when those parts are properly sequenced?

David: Genetically inclined students of human biology, medicine, and evolution tend to focus their efforts on the parts of the genome that are most readily analyzed – the civilized, single-copy parts that approach most closely our Mendelian expectations. But there is so much to be learned in the relatively understudied and untamed parts of the genome where palindromes, amplicons, and segmental duplications bend the rules, demanding special attention to technical and analytic matters but offering rich rewards to the curious and persistent.

AJHG: What advice do you have for trainees/young scientists?

Levi: I’m a trainee and a young scientist myself, so I don’t have much career experience to draw upon, but my advice would be to never forget the human factor when choosing what to work on and who to work with. If you are surrounded by good people and you enjoy working with them, your science will be better for it.

David: Work with people whom you like, respect, and admire, on questions that you personally find to be compelling. Nothing is more satisfying than finding value and meaning where others think not to look.

AJHG: And for fun, tell us something about your life outside of the lab.

Levi: I’m an amateur baker and have recently started accumulating kitchen gadgets, including a doughnut filling injector, a rotating cake stand, and a frying pan just for blintzes.

David: I love to explore the outdoors, and especially mountains and lakes, with family and friends, in all seasons. I would point out that some of our oldest and most acclaimed National Parks – Yellowstone and Yosemite – begin with the letter Y.

A longtime member of ASHG, David Page, MD, is Director of the Whitehead Institute, Professor of Biology at the Massachusetts Institute of Technology and Howard Hughes Medical Institute Investigator.

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