연구소 자리를 알아보는 와중 .. 이번 학기 들었던 면역학 강의 범위와 겹치는 연구를 만났다. 교수도 여섯이나되고 내용도 세부적이고 시험지가 무려 열여섯 장이었지만 예상외로 성적을 올려준 수업. 조교 열성이 큰 몫 했다. 

Fred Hutchinson Cancer Research Center 에서 진행중인 종형성에 있어 centromere 의 영향, 그 상당성에 비해 작은 안정성 - 그리고 궁극적으로 그것의 발암 가능성. 

Fred Hutchinson Cancer Research Center
1100 Fairview Ave. N. PO Box 19024 Seattle, WA 98109
©2012 Fred Hutchinson Cancer Research Center, a 501(c)(3) nonprofit organization.

http://labs.fhcrc.org/malik/ 

Evolutionary arms-races

The Red Queen: “It takes all the running you can do, to keep in the same place.”--Lewis Carroll, “Through the Looking Glass”

The Red Queen Hypothesis: “For an evolutionary system, continuing development is needed just in order to maintain its fitness relative to the systems it is co-evolving with.” --Leigh Van Valen (1973)

Our genomes are a tenuous conglomerate of different genetic entities, each trying to maximize their own evolutionary success, often at great cost to their genomic neighbors. As expected, this conflict can create problems for the host organism. My lab is interested in evolutionary studies of genetic conflict to gain insight into their mechanisms and consequences. We study genetic conflicts primarily in three systems: Drosophila, primates and yeast. While there are a number of investigative projects that are going on at any given time in the lab, our focus is on three conflicts in particular:

• centromeres
• innate and intrinsic immunity against viruses in primates
• mobile genetic elements in Drosophila.

More information about each of these projects and the rationale behind them can be found on our "Projects" page.

The centromere paradox: stable inheritance with rapidly evolving DNA

Centromeres are sites of spindle attachment to chromosomes at mitosis and meiosis, and are crucial for the stable inheritance of all eukaryotic chromosomes. Defects in this segregation machinery are responsible for aneuploidy events, which may also lead to cancer. The simplest known centromeres of the budding yeast Saccharomyces cerevisiae have a 125 bp consensus which are each packaged in a single nucleosome containing the centromeric histone Cse4 instead of H3. However, this simplicity is atypical of other eukaryotes, in which centromeric repeats comprise the most rapidly evolving DNA sequences in eukaryotic genomes, differing even between closely related species. These satellite changes are brought about by a variety of mutational processes, including replication slippage, unequal exchange, transposition and excision. Such rapid change is paradoxical: why hasn't a single optimal sequence been fixed at centromeres given its essential role in faithful segregation of chromosomes?

We have investigated this question by studying the evolutionary history of histone H3-like centromeric histones (including Cenp-A in mammals). Comparison of the H3-like centromeric histone Cid from closely related Drosophilaspecies reveals that both the N-terminal tail and the histone core domain contain regions that have undergone frequent episodes of adaptive evolution, where a greater than expected amino acid replacement changes have become fixed between the two species, D. melanogaster and D. simulans. This is unexpected for a histone molecule, as histones are among the most evolutionarily constrained eukaryotic proteins. Within the histone core domain, most adaptive changes lie in loop 1, a region that makes direct H3-DNA contacts, suggesting that centromeric histone binding is sequence dependent. The adaptive signal and its location provide compelling evidence that Cid has evolved in concert with centromeric DNA. Understanding the basis of these adaptive changes could resolve the paradox of rapidly evolving centromeres.

We suggest that asymmetry at female meiosis may be the key. Of the four products of meiosis, three are lost and only one becomes the oocyte nucleus. There is evidence that the asymmetry of the meiotic tetrad provides an opportunity for chromosomes to compete for inclusion into the oocyte nucleus by attaining a preferable orientation at the meiosis. Centromeres that can exploit this opportunity at meiosis I will “win”, and even a slight advantage at each female meiosis is enough to rapidly drive a centromere to fixation. Additional recruitment of centromeric nucleosomes, for example, by the expansion of a centromeric satellite, would confer this advantage (Figure). Genetic evidence that some animal and plant centromeres are “stronger” at meiosis dates back nearly half a century. In maize, centromere strength is characteristic of heterochromatic “knobs”, which display poleward movement and meiotic drive during female meiosis, and a similar drive process might contribute to the success of selfish B chromosomes. In humans, a variety of Robertsonian translocations, with two adjacent centromeres, consistently display a higher than expected transmission ratio.

In females, these “winning centromeres” simply exploit the inherently destructive process of forming the egg, and thus might not reduce fecundity. However, in Drosophila males, heterochromatic differences between paired chromosomes at meiosis I can cause non-disjunction manifested as skewed sex ratios or infertility. We propose that these chromosome pairs have centromeric imbalances. Cid is the best candidate to relieve deleterious effects associated with centromere meiotic drive. For example, if Cid were to mutate such that it preferentially bound the weaker centromere, centromeric balance would be restored (Figure). Such a beneficial cid allele will drive to fixation itself. This two-step process (Figure) suffices to explain both the evolutionary dynamics of satellite DNA and the adaptive evolution of Cid. Episodes of drive and deleterious mutation by transposons would lead to the accumulation of satellites representing centromeric relics surrounding functional centromeres. This would also provide a mechanism for the well-documented fixation of chromosome-specific satellites in successive episodes of drive.

Consider this process occurring in two isolated populations of the same species. Satellite-Cid configurations will diverge rapidly. In each population, Cid will evolve to suppress the deleterious effects of satellites that have driven through that population. By so doing, Cid becomes incompatible with the independently evolving centromeric satellites in the other population. Crosses between the populations will result in hybrid defects as centromeric drive is released again. Thus, the satellite-Cid drive process results in the onset of reproductive isolation between the two populations. In other words, speciation is an inevitable consequence of centromere evolution.

We are currently testing this model using recently diverged species of Drosophila.

Centromere drive model. Expansion of a satellite that binds Cid provides more microtubule attachment sites. This stronger centromere drives in female meiosis, but also leads to increased non-disjunction. A mutation in Cid that alters sequence specificity leads to more extensive binding of the weaker centromere, providing more microtubule attachment sites. This restores meiotic balance and alleviates non-disjunction.

http://labs.fhcrc.org/malik/projects.html 

What we work on . . . .

Our genomes are a tenuous conglomerate of different genetic entities, each trying to maximize their own evolutionary success, often at great cost to their genomic neighbors. As expected, this conflict can create problems for the host organism. My lab is interested in evolutionary studies of genetic conflict to gain insight into their mechanisms and consequences. For this purpose, we study centromeres, mobile genetic elements and rapidly evolving proteins in Drosophila.     are crucial for the faithful segregation of genetic information in eukaryotes, but they remain the most mysterious part of our genomes. In both animal and plant meiosis, in the process of forming an egg, of four meiotic products, only one becomes the egg, while the other three are evolutionary dead-ends. There is intense competition between various chromosomes, likely through their centromeres for success into the egg. Our hypothesis is that this results in the rapid gain of centromeric satellites often with deleterious consequences to the host. For instance, in humans, Robertsonian fusions (chromosomes fused at their centromeres) are transmitted more frequently in women, but male carriers of these fusions are partially to completely sterile. We study the rapid evolution of centromeric components to gain a better understanding of aneuploidy events (commonly observed in cancer cells) and to answer one of the long-standing questions in biology: how do two species evolve from one? (read more)     genetic elements are ubiquitous and constitute large fractions of eukaryotic genomes. They are the classical example of genomic 'mercenaries', interested in their own evolutionary success. We study the evolutionary origins of different classes of transposable elements and their consequences to host fitness and genome organization. We have been concentrating on the evolutionarily and medically important transition of a non-viral retrotransposon to an infectious retrovirus, using models in Drosophila and C. elegans. I have discovered a Drosophila host gene (Iris) homologous to the envelope genes of both insect baculoviruses and the gypsy and roo retroviral lineages. This gene has been present as a host gene in insect genomes for at least 250 million years (since the origin of Diptera) and may play a crucial role in membrane transport in female oogenesis. We are also studying the evolution of innate defense strategies against retroviruses in primate genomes (collaboration with Michael Emerman)     have been found as a consequence to genetic conflict, including host-parasite interactions (ex. Immunoglobulin, viral envelopes). Recent studies have found that a large number of ''speciation'' genes encode either DNA-binding proteins or even components of the nuclear pore complex. My lab has initiated cytological and functional studies with the ultimate aim of understanding what selective pressures drive the adaptive evolution of these classical intra-cellular proteins (i.e. what genetic conflict are they subject to). This will further our understanding of the role selection plays in the shaping of our genomes, and potentially expand the list of categories to which rapidly evolving proteins can belong.