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Developmental Biology - Meiosis
In Meiosis Short & Long Chromosomes Compete
Small chromosomes must compete with big ones during cell division...
From avocado plants to baker's yeast, humans to zebras, organisms that reproduce sexually must create their germ cells - sperm and egg. Each of these germ cells contain half the chromosomes found in body cells. When germ cells combine during fertilization, the number of chromosomes for that organism is restored in the now fertilized egg.
The process that produces germ cells is a type of cell division called meiosis. As a result of meiosis, each germ cell contains only one copy from each of the parents' chromosomes. (In humans, that's 23 chromosomes versus the usual 46 in a body cell).
Meiosis reduces the number of chromosomes, and also shuffles the genes from the maternal and paternal chromosomes. Chromosomes are broken apart to swap segments by crossing over one another, then divvied up into daughter cells. This shuffling of chromosome segments is why you and your siblings look different despite having the same parents. The sperm and egg that came together to make you and your siblingscontained a unique combination of maternal and paternal chromosomes.
Meiosis is one of the most important processes in all of biology, yet much about it remains curious. A particular long standing question is how do small chromosomes not get lost in the breaking and recombining of chromosome strands — when some of these chromosome segments are ten times the size of others?
"We've known for a while that smaller chromosomes have a higher rate of DNA double-strand breaks - which initiate recombination," explains Scott Keeney, a molecular biologist in the Sloan Kettering Institute and also a newly elected member of the National Academy of Sciences. "But it was unclear how small chromosomes 'punch above their weight' in making these breaks."
Now, Keeney and a team from his lab have solved the puzzle. A new paper describing their findings published May 6 in the journal Nature.
Don't You Forget about Me
For chromosomes, recombination is not only a means of genetic diversity. It is crucial to their accurate segregation into germ (sex) cells.
Random segregation can result in the unequal distribution of chromosomes. Called aneuploidy, the wrong number of chromosomes in an egg or sperm is a main cause of birth defects.
The first step in recombination is breaking apart the two strands of the DNA double helix, called a double-strand break (DSB). Special proteins — including one called Spo11, which Dr. Keeney discovered more than two decades ago — create DSBs in chromosomes. The maternal and paternal members of each chromosome pair then find one another, and the non-broken chromosome is used as a template to repair the break in the broken chromosome.
After this process of breaking and repair, maternal and paternal chromosomes are essentially tied together, such that if you pulled on one you would bring its partner with it. It turns out that this temporary tying of the knot is crucial to how cells know that the two members of the chromosome pair are ready to be split up into different cells. Therefore, every chromosome pair needs at least one DSB to ensure it gets properly segregated.
"If DSB formation were a random process, happening blindly across all chromosomes, then you would expect that very small chromosomes would sometimes get skipped over," Dr. Murakami says. "But that does not typically happen."
If fact, Dr. Murakami explains that small chromosomes have a higher rate of breaking and recombining than longer chromosomes for a given length of DNA. By recruiting more of the proteins that break chromosomes to initiate recombination, and holding on to them for longer, little chromosomes ensure they aren't forgotten.
Giving Small Chromosomes a Boost
The researchers came to their conclusions through a series of elegant experiments conducted in the yeast Saccharomyces cerevisiae, a simple eukaryotic organism with 16 chromosomes, including three that are very small. In one experiment, researchers wanted to know what would happen if a short chromosome was made long by attaching it to a longer neighbor. Would it still behave like a short chromosome and recruit the breaking factors? The answer was YES.
They also asked what would happen if you made a long chromosome short — by chopping it in half. Would it behave like a short chromosome? It did not. These results strongly suggest there is an unknown factor in little chromosomes which determines its behavior — not its size.
This extra "boost" helps explain why small chromosomes 'punch above their weight', ensuring that all chromosome can recombine no matter how small.
Abstract
In most species, homologous chromosomes must recombine in order to segregate accurately during meiosis1. Because small chromosomes would be at risk of missegregation if recombination were randomly distributed, the double-strand breaks (DSBs) that initiate recombination are not located arbitrarily2. How the nonrandomness of DSB distributions is controlled is not understood, although several pathways are known to regulate the timing, location and number of DSBs. Meiotic DSBs are generated by Spo11 and accessory DSB proteins, including Rec114 and Mer2, which assemble on chromosomes3,4,5,6,7 and are nearly universal in eukaryotes8,9,10,11. Here we demonstrate how Saccharomyces cerevisiae integrates multiple temporally distinct pathways to regulate the binding of Rec114 and Mer2 to chromosomes, thereby controlling the duration of a DSB-competent state. The engagement of homologous chromosomes with each other regulates the dissociation of Rec114 and Mer2 later in prophase I, whereas the timing of replication and the proximity to centromeres or telomeres influence the accumulation of Rec114 and Mer2 early in prophase I. Another early mechanism enhances the binding of Rec114 and Mer2 specifically on the shortest chromosomes, and is subject to selection pressure to maintain the hyperrecombinogenic properties of these chromosomes. Thus, the karyotype of an organism and its risk of meiotic missegregation influence the shape and evolution of its recombination landscape. Our results provide a cohesive view of a multifaceted and evolutionarily constrained system that allocates DSBs to all pairs of homologous chromosomes.
Authors
Hajime Murakami, Isabel Lam, Pei-Ching Huang, Jacquelyn Song, Megan van Overbeek and Scott Keeney.
Acknowledgements
The authors thank A. Viale and N. Mohibullah of the Memorial Sloan Kettering Cancer Center (MSKCC) Integrated Genomics Operation for DNA sequencing; N. Socci at the MSKCC Bioinformatics Core Facility for mapping ChIP–seq and Spo11-oligo reads; and members of the Keeney laboratory, especially S. Yamada for advice on data analysis and L. Acquaviva for sharing unpublished information. We thank V. Subramanian, A. Hochwagen and F. Klein for discussions and for sharing unpublished information; and M. Lichten, E. Louis, K. Ohta, A. Amon, W. Zachariae, J. Matos and R. Rothstein for strains or plasmids. I.L. and M.v.O. were supported in part by National Institutes of Health (NIH) fellowships F31 GM097861 and F32 GM096692, respectively. This work was supported by NIH grants R01 GM058673 and R35 GM118092 to S.K. MSKCC core facilities are supported by NCI Cancer Center Support Grant P30 CA008748.
About Memorial Sloan Kettering (MSK):
As the world's oldest and largest private cancer center, Memorial Sloan Kettering has devoted more than 135 years to exceptional patient care, influential educational programs and innovative research to discover more effective strategies to prevent, control and, ultimately, cure cancer. MSK is home to more than 20,000 physicians, scientists, nurses and staff united by a relentless dedication to conquering cancer. Today, we are one of 51 National Cancer Institute-designated Comprehensive Cancer Centers, with state-of-the-art science and technology supporting groundbreaking clinical studies, personalized treatment, and compassionate care for our patients. We also train the next generation of clinical and scientific leaders in oncology through our continually evolving educational programs, here and around the world. Year after year, we are ranked among the top two cancer hospitals in the country, consistently recognized for our expertise in adult and pediatric oncology specialties. http://www.mskcc.org.
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May 7 2020 Fetal Timeline Maternal Timeline News
 Fig. 4: The role of axis proteins in the short chromosome boost and an integrated view of double strand break (DSB) control. CREDIT the authors.
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