When a woman becomes pregnant, the outcome of that pregnancy depends on many things \u2014 including a crucial event that happened while she was still growing inside her own mother\u2019s womb. It depends on the quality of the egg cells that were already forming inside her fetal ovaries. The DNA-containing chromosomes in those cells must be cut, spliced and sorted perfectly. In males, the same process produces sperm in the testes but occurs only after puberty.<\/p>\n
\u201cIf that goes wrong, then you end up with the wrong number of chromosomes in the eggs or sperm,\u201d said Neil Hunter, a professor in the Department of Microbiology and Molecular Genetics at UC Davis. \u201cThis can result in infertility, miscarriage or the birth of children with genetic diseases.\u201d<\/p>\n
In a paper published Sept. 24 in the journal\u00a0Nature, Hunter\u2019s team\u00a0reports a major new discovery about a process that helps safeguard against these mistakes. He has pieced together the choreography of proteins that connect matching chromosome pairs \u2014 ensuring that they are sorted correctly as egg and sperm cells develop and divide.<\/p>\n
Hunter\u2019s discoveries required methods to watch the molecular events of chromosome recombination unfold with unprecedented detail. This involved genetic engineering in budding yeast \u2014 a model organism that has been used for decades to discover how fundamental cellular processes work.<\/p>\n
\u201cThe chromosome structures that we studied have changed very little across evolution,\u201d Hunter said. \u201cEvery protein that we looked at in yeast has a direct counterpart in humans.\u201d His findings could improve our understanding of fertility problems and how they are diagnosed and treated in humans.<\/p>\n
Forming chromosome crossovers for strong connections<\/p>\n
Humans have 46 chromosomes in each of our cells, made up of 23 pairs of matching, \u201chomologous\u201d chromosomes, with one of each pair inherited from each parent. Early in the process of making sperm or eggs, those chromosome pairs line up, and the parental chromosomes break and rejoin to each other. These chromosome exchanges, called \u201ccrossovers,\u201d serve two important functions.<\/p>\n
First, they help ensure that each chromosome that is passed on to the offspring contains a unique mixture of genes from both parents. Crossovers also keep the chromosomes connected in matching pairs. These connections guide the distribution of chromosomes when cells divide to produce eggs and sperm. Maintaining crossover connections is especially crucial in females, Hunter said.<\/p>\n
As chromosomes pair up in developing egg or sperm cells, matching DNA strands are exchanged and twined together over a short distance to form a structure called a \u201cdouble Holliday junction.\u201d DNA strands of this structure are then cut to join the chromosomes forming a crossover.<\/p>\n
In males, developing immature sperm cells immediately divide and distribute their chromosomes to form sperm. In contrast, egg cells developing in the fetal ovary arrest their development after crossovers have formed. The immature egg cells can remain in suspended animation for decades after birth, until they are activated to undergo ovulation.<\/p>\n
Only then does the process lurch back into motion: The egg cell finally divides, and the chromosome pairs that were connected by crossovers are finally separated to deliver a single set of chromosomes to the mature egg. \u201cMaintaining the crossover connections over many years is a major challenge for immature egg cells,\u201d Hunter said.<\/p>\n
If chromosome pairs aren\u2019t connected by at least one crossover, they can lose contact with each other, like two people separated in a jostling crowd. This causes them to segregate incorrectly when the cell finally divides, producing egg cells with extra or missing chromosomes. This can cause infertility, miscarriage or genetic conditions such as Down syndrome, in which a child is born with an extra copy of chromosome 21, leading to cognitive impairment, heart defects, hearing loss and other problems.<\/p>\n
From yeast to humans<\/p>\n
Hunter has spent years trying to understand how crossovers form and how this process can fail and cause reproductive problems. By studying this process in yeast, researchers can directly visualize molecular events of double-Holliday junction resolution in synchronized populations of cells.<\/p>\n
Researchers have identified dozens of proteins that bind and process these junctions. Hunter and then-postdoctoral fellow Shangming Tang (now an assistant professor of biochemistry and molecular genetics at the University of Virginia) used a technique called \u201creal-time genetics\u201d to investigate the function of those proteins. With this method, they made cells degrade one or more specific proteins within the junction-associated structures. They could then analyze the DNA from these cells, to see whether the junctions were resolved and if they formed crossovers. In this way, they built up a picture in which a network of proteins function together to ensure that crossovers are formed.<\/p>\n
\u201cThis strategy allowed us to answer a question that previously wasn\u2019t possible,\u201d Hunter said.<\/p>\n
They identified key proteins such as cohesin that prevent an enzyme called the STR complex (or Bloom complex in humans) from inappropriately dismantling the junctions before they can form crossovers.<\/p>\n
\u201cThey protect the double Holliday junction,\u201d Hunter said. \u201cThat is a key discovery.\u201d<\/p>\n
This years-long research project in yeast is broadly relevant for human reproduction because the process has changed very little during evolution. Failure to protect double-Holliday junctions may be linked to fertility problems in humans.<\/p>\n
In addition to Tang, the postdoc, seven undergraduates in the UC Davis College of Biological Sciences contributed to this work, including Jennifer Koo, Mohammad Pourhosseinzadeh, Emerald Nguyen, Natalie Liu,\u00a0Christopher Ma, Hanyu Lu and Monica Lee.<\/p>\n
Additional authors on the paper include Sara Hariri, Regina Bohn and John E. McCarthy, all members of the Hunter lab.<\/p>\n
Hunter\u2019s research is funded by the National Institutes of Health and the Howard Hughes Medical Institute. His work has also received funding from the UC Davis\u00a0Comprehensive Cancer Center, the American Cancer Society, the Concern Foundation for Cancer Research, and the Damon Runyon Cancer Foundation.<\/p>\n
Hunter\u2019s research on crossover and homologous recombination uses advanced scientific facilities at the university\u2019s\u00a0Proteomics Core Facility,\u00a0MCB Light Microscopy Imaging Facility,\u00a0Genome Center,\u00a0Mouse Biology Program, and the\u00a0Comprehensive Cancer Center.<\/p>\n
By Douglas Fox | UC Davis News Service<\/p>\n","protected":false},"excerpt":{"rendered":"When a woman becomes pregnant, the outcome of that pregnancy depends on many things \u2014 including a crucial…\n","protected":false},"author":2,"featured_media":41395,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[7],"tags":[631,85,46,869,224,43,3645,141,33215],"class_list":{"0":"post-41394","1":"post","2":"type-post","3":"status-publish","4":"format-standard","5":"has-post-thumbnail","7":"category-science","8":"tag-community","9":"tag-il","10":"tag-israel","11":"tag-latest-headlines","12":"tag-local-news","13":"tag-news","14":"tag-newsletter","15":"tag-science","16":"tag-uc-davis"},"_links":{"self":[{"href":"https:\/\/www.newsbeep.com\/il\/wp-json\/wp\/v2\/posts\/41394","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.newsbeep.com\/il\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.newsbeep.com\/il\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/il\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/il\/wp-json\/wp\/v2\/comments?post=41394"}],"version-history":[{"count":0,"href":"https:\/\/www.newsbeep.com\/il\/wp-json\/wp\/v2\/posts\/41394\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/il\/wp-json\/wp\/v2\/media\/41395"}],"wp:attachment":[{"href":"https:\/\/www.newsbeep.com\/il\/wp-json\/wp\/v2\/media?parent=41394"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.newsbeep.com\/il\/wp-json\/wp\/v2\/categories?post=41394"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.newsbeep.com\/il\/wp-json\/wp\/v2\/tags?post=41394"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}