Enter the synaptonemal complex (SC), a zipper-like protein structure that lines up and anchors the two parental chromosomes together, end-to-end, to facilitate successful genetic exchanges. Failure to regulate this exchange is a leading cause of age-related infertility in humans and could compromise fertility across the tree of life. Humans, fungi, plants, worms and anything that reproduces sexually uses the SC to make reproductive cells, known as gametes. Despite its importance, we don’t understand how proteins within the SC regulate chromosomal interactions because this multi-step process happens in internal organs and has been impossible to recreate in a lab.

In a new study, University of Utah biologists developed a method for illuminating the intricate interactions of the SC in the nematode C. elegans. The authors identified a trio of protein segments that guide chromosomal interactions, and pinpointed the location where they interact with each other. Their novel method uses a technique known as genetic suppressor screening, which can serve as a blueprint for research on large cellular assemblies that resist traditional structural analysis.

“This is a way to lock in on systems in cells that are too ‘loosie-goosey’ to use methods that rely on crystallization,” said Ofer Rog, associate professor of biology at the U and senior author of the study. “A lot of the interactions in cells are loosely bonded together. The problem is that you can’t look at it under an electron microscope because nothing is stable enough — everything is constantly moving. Our approach allows you to study even the interactions that are relatively weak or transient.”

The study published on Dec. 6, 2023, in the journal Proceedings of the National Academy of Sciences (PNAS).

The birds and the bees… and the nematodes

Let’s dig into meiosis. Chromosomes are thread-like structures made of DNA that carry genetic information when cells divide and from generation to generation. Regular cells have a certain number of chromosomes; humans have 46 and C. elegans have 12. Chromosomes come in pairs called homologous chromosomes that carry the genes we inherited from each of our parents — one from our mom, one from our dad. When meiosis begins, homologous chromosomes arrange themselves into elongated structures organized along a backbone called the axis. The axes of homologous pairs are aligned lengthwise to each other while at the same time, the synaptonemal complex (SC) forms between the parallel axes. The homologous pairs have matching genes arranged in the same order, with small variations within the genes — these are the variations that make each individual unique.

“You can think of it like a zipper,” Rog explained. “The axes of the chromosomes are like the two sides of your shirt. The synaptonemal complex is kind of like the teeth of the zippers that lock onto each other and can pull and align the two sides of the shirt correctly.”

Scientist previously knew that the SC of C. elegans formed between homologs, but the U biologists are the first to pinpoint the exact position where the SC interacts with itself to facilitate genetic exchanges.

“When you exchange information between the chromosomes, you want to make sure that at the end you still have two complete chromosomes,” said Rog. “The way the cell does it is that the two chromosomes are perfectly aligned. So, when you exchange segments between them, you’re not losing any information in the process.

How to analyze loosie-goosey structures

The researchers bred 50,000 nematodes that had temperature-sensitive defects in the SC. At high temperatures, the worms were unable to form the SC protein zipper needed to join the chromosomes together. Without the zipper, the gene exchanges during meiosis either didn’t happen at all or didn’t occur at the right number. Lisa Kursel, postdoctoral researcher and lead author of the study ran the experiments.

“We grew the worms at the permissive, cooler temperature, then exposed them to a chemical that caused millions of mutations along their chromosomes and watched to see if any of the mutated worms could reproduce at the warmer temperature,” Kursel said. The chemically induced mutations that corrected the nematode’s infertility are known as suppressor mutations. “Then we’d know if the suppressor mutations restored their fertility.”

To identify the animals with mutations that made them fertile again, the researchers put the nematodes on agar plates filled with yummy bacteria. The agar plates that had fertile nematodes were soon empty as their progeny ate the food. The agar plates with sterile worms died off before they could clean their plate, allowing the bacteria to flourish.

Once they had fertile nematodes, they could test if the mutation “fixed” the protein zipper. They then screened every single base pair on the DNA — 100 million base pairs — and identified which mutations restored the worms’ ability to reproduce. They found that all the helpful mutations occurred in short segments of three proteins, SYP-1, SYP-3, SYP-4. Moreover, the mutations carried distinct signatures of interaction. For example, while the original mutations changed the electric charge from positive to negative, the helpful mutations flipped the charge back.

“This was a strong indication that SYP-1, SYP-3 and SYP-4 interact with each other like magnets, with positive and negative regions attracted to each other,” said Rog. Such “sticky” interactions could also help tether the chromosomes together.

Jesus Aguayo Martinez, a senior biology major and co-author of the study, looked at the behavior of the suppressor mutation in nematodes without the original SC-disrupting mutation.

“We thought that since the original mutation alone produced a fertility defect, then the nematodes with the suppressor mutation alone would also have a fertility defect. That wasn’t the case,” said Aguayo Martinez. “Surprisingly, normal worms and worms with only the suppressor mutations produced similar numbers of progeny.”

Next steps

Uncovering the SC’s role in meiosis may help to better understand fertility in humans. The SC has a similar role across all eukaryotes, from nematodes to fungi to plants to humans. Previous research by the Rog Lab at the U showed that the structure itself looks the same and acts similarly to bring in parental chromosomes to facilitate exchanges. However, the actual sequences of the protein components are different between organisms. Such a pattern is unusual: Most cellular structures that carry essential, basic functions like cell division, genome duplication or metabolism are highly conserved, and could in fact be swapped between different organisms.

“A question that we think a lot about is what is special about the SC? Why can it do the same thing and look the same way, but consist of different building blocks?” Rog asked.

Kursel, Aguayo Martinez, Rog and other members of the lab are doing more analysis on the evolution of the SC across species, and of other cellular structures that defy the common wisdom of evolution.

This work was funded by the National Institute for General Medical Sciences grant R35GM128804. Kursel was supported by the Developmental Biology Training Grant from the U.S. National Institute of Child Health and Human Development, and Aguayo Martinez was supported by a University of Utah Biology Research Scholar Award.

In a paper published this week in the Proceedings of the National Academy of Sciences, a team of scientists demonstrated that kelp forests can do more than supply food to tiny, hungry crustaceans living in the sand. They can also influence the dynamics of the sandy beach food web.

“The amount of kelp on the reef changes through time in a way where the peaks and low points in abundance across several kelp forests are matched together,” said lead author Jonathan Walter, a senior researcher at the University of California, Davis, and its Center for Watershed Sciences. “That’s what we refer to as synchrony. It is related to the ability of systems to persist in the face of changing environmental conditions. A little asynchrony allows systems to be resistant to fluctuations and therefore more stable.”

The study uncovers the role of synchrony in the beach food web, with broader implications as the climate shifts in ways that might change how linked ecosystems perform their functions.

Revealing synchrony’s role in these ecosystems fills a key knowledge gap in our understanding of the connection of reef and beach.

“The kelp forest and the beach are both highly dynamic ecosystems,” said co-author Jenny Dugan, a coastal marine ecologist at UC Santa Barbara. “How the dynamics of those two ecosystems interact and behave is the key question here, especially with the beach system so dependent on the kelp forest.”

In sync

Though a natural and ubiquitous phenomenon, synchrony and its implications are not yet fully understood.

The research team sought to understand whether and how kelp wrack (detritus) could affect the beach ecosystem’s dynamics. For instance, how might species respond to the changing environment, and how resilient is the beach ecosystem to disturbances?

To address these questions, the study used long-term data from UCSB’s Santa Barbara Coastal Long Term Ecological Research site, which is supported by the National Science Foundation. The team’s model was built on a time series of wind, wave, wrack, and beach-width data at five sandy beaches over 11 years.

It revealed patterns of synchrony — where the abundance of kelp wrack on beaches could be explained by kelp abundance in the forest, wave action, and beach width fluctuating together. At the longest timescales, kelp forest biomass and beach width were the biggest drivers of kelp wrack on the beaches.

Beach melodies

“We found time lags in this synchrony that were important,” Dugan said. “It wasn’t as simple as everything changing at the same time — it was like separate songs or melodies that came together in different ways. This made the patterns more complex, which is why it required the type of analyses we used.”

Importantly, the researchers found this synchrony crossed from ocean to shore. The abundance of predatory shorebirds, like sandpipers and plovers, lagged behind the deposition of wrack on beaches.

“Once on the beach, kelp wrack feeds a highly productive community of small invertebrates — crustaceans and insects — that are in turn a favorite food of shorebirds,” Dugan explained. The cross-system synchrony is particularly notable because the beach ecosystem relies so heavily on kelp subsidies, she added.

Dynamic nature

“The dynamic nature of kelp forests, in terms of their high productivity and turnover, is unique for ecosystems structured around foundation species,” said co-author and coastal ecologist Kyle Emery, a researcher in the UCSB Marine Science Institute. “It allows us to observe change many times over compared to other foundation species and gives us the ability to observe many different system states, processes and functions. This enabled us to more rapidly analyze these questions of cross-ecosystem synchrony.”

The study was funded by the Santa Barbara Coastal Long Term Ecological Research, National Science Foundation, McDonnell Foundation and Humboldt Foundation.

“Given that signs of Alzheimer’s disease start to accumulate in the brain several decades before symptoms begin, understanding the connection between sleep and cognition earlier in life is critical for understanding the role of sleep problems as a risk factor for the disease,” said study author Yue Leng, PhD, of the University of California, San Francisco. “Our findings indicate that the quality rather than the quantity of sleep matters most for cognitive health in middle age.”

The study involved 526 people with an average age of 40. They were followed for 11 years.

Researchers looked at participants’ sleep duration and quality. Participants wore a wrist activity monitor for three consecutive days on two occasions approximately one year apart to calculate their averages. Participants slept for an average of six hours.

Participants also reported bedtimes and wake times in a sleep diary and completed a sleep quality survey with scores ranging from zero to 21, with higher scores indicating poorer sleep quality. A total of 239 people, or 46%, reported poor sleep with a score greater than five.

Participants also completed a series of memory and thinking tests.

Researchers also looked at sleep fragmentation, which measures repetitive short interruptions of sleep. They looked at both the percentage of time spent moving and the percentage of time spent not moving for one minute or less during sleep. After adding these two percentages together, researchers found that participants had an average sleep fragmentation of 19%.

Researchers then divided participants into three groups based on their sleep fragmentation score.

Of the 175 people with the most disrupted sleep, 44 had poor cognitive performance 10 years later, compared to 10 of the 176 people with the least disrupted sleep.

After adjusting for age, gender, race, and education, people who had the most disrupted sleep had more than twice the odds of having poor cognitive performance when compared to those with the least disrupted sleep. There was no difference in cognitive performance at midlife for those in the middle group compared to the group with the least disrupted sleep.

“More research is needed to assess the link between sleep disturbances and cognition at different stages of life and to identify if critical life periods exist when sleep is more strongly associated with cognition,” Leng said. “Future studies could open up new opportunities for the prevention of Alzheimer’s disease later in life.”

The amount of time people slept and their own reports of the quality of their sleep were not associated with cognition in middle age.

A limitation of the study was that due to the small sample size, researchers were unable to fully investigate potential race or gender differences.

The study was funded by the National Institute on Aging and the National Heart, Lung, and Blood Institute.

“To understand the root causes of this disparity and potential solutions, UH faculty, staff and students approached this problem through the lens of voyagers, examining the past course of history of the peoples of the Pacific and attempts to make headwinds in programs focused on increasing participation in ocean sciences,” said co-author Rosie Alegado, associate professor in the UH Mānoa School of Ocean and Earth Science and Technology (SOEST).

The article highlights programs in SOEST that are aimed at reducing barriers for Native Hawaiians in the geosciences — including summer bridge programs, internships, and other professional development programs. And, in better defining the persistent, systemic, and collective barriers that NHPI face within the western society and the academy, the authors identify gaps that conventional professional development programs aimed at minoritized groups in the geosciences have been unsuccessful in filling.

“One of the biggest gaps that we found related to Native Hawaiian-serving programs within the ocean sciences is that while many may be culturally based, few are Native Hawaiian led,” said lead author Haunani Kane, SOEST assistant professor. “Native Hawaiians are often overlooked in the development and leadership of Native Hawaiian and Pacific Islander-serving programs. Programs led by Native Hawaiian scientists and community members ensure that they are culturally centered safe spaces for students to collectively grow their identities as both Native Hawaiians and scientists.”

Importantly, the authors shared lessons learned from building two waʻa (canoes)-programs specifically designed to carry students forward toward futures that center oceanic ways of knowing.

SOEST Maile Mentoring Bridge

The SOEST Maile Mentoring Bridge program (Maile) was founded in 2013 with the goal of attracting and retaining more NHPIs into geoscience degree programs and careers. The foundation of Maile was to build and foster robust partnerships with neighboring community colleges within the UH system. Maile mentees are carefully paired with experienced mentors — SOEST graduate students, postdocs, or recent graduates.

“Looking back on the last 10 years of my life, the Maile Mentoring program has made such a huge impact,” said Diamond Tachera, study co-author and alumni and co-director of Maile. “As an undergraduate student, it was so important for me to see people, especially wāhine (women), who looked like me working and thriving in their scientific fields. Being part of the Maile ʻohana as a graduate student mentor also helped me to build confidence in myself as I continued to struggle to find my place and identity in academia. I will be forever grateful for the support and aloha that comes with being part of the Maile ʻohana.”

“I believe the Maile Mentoring program has been successful because it places an emphasis on meeting the needs of the whole student, not just their research endeavors,” said Alegado. “In focusing on creating a nurturing environment in SOEST, we place a stronger emphasis on retention of students, not just recruitment, which increases completion and graduation rates for NHPI.”

The MEGA Lab

To overcome traditional barriers related to retention of NHPIs in the ocean sciences, the multiscale environmental graphical analysis (MEGA) Lab, a predominantly Native Hawaiian-led lab and nonprofit physically located in Hilo, Hawai’i, developed a research program that prioritizes inclusive research experiences. Foundational to their success has been incorporating community members and cultural values into research projects, and creating global partnerships that value Native Hawaiian research.

As a way to creatively explore what Native science and kuleana (responsibility) could look like if research and cultural priorities were equally weighted in all aspects of the research design, the MEGA Lab assembled a Native Hawaiian research team to embark on a 15-day voyage to Papahānaumokuākea Marine National Monument.

“That trip inspired me to re-imagine what research looks like when it’s grounded in our ʻōiwi perspectives and how I can contribute to create more room for that to happen,” said Kainalu Steward, graduate student in the SOEST Department of Earth Sciences. “That experience helped me find kuleana in this collective work at the monument and reinforced my interest in pursuing higher education.”

Looking to the horizon

“Moving forward, we believe that in order to make progress in the representation, retainment, and success of Native Hawaiians and Pacific islanders in STEM, we must first address the historical and ongoing traumas of Native Hawaiians and Pacific Islanders through active engagement in reclamation of cultural identities and knowledge,” said Kane. “We also believe student success requires building community support systems both within and beyond UH where students can safely explore their whole identity as Indigenous scientists.”

The MEGA Lab founders are also calling for a culture change in academia and their “experiment to disrupt the hierarchical and stereotypical structures that exist in science and act as barriers to inclusion,” as they write in a second article in the special issue of Oceanography, provides a template. “Our goal was to create an interdisciplinary and inter-institutional lab that promotes an inclusive, equitable, and uplifting team environment where everyone can thrive in a fun and productive workspace.”

“All of the work we do to support Native Hawaiians, women, and other underrepresented groups (the fish) can only have limited success given our current toxic workplace culture (the fishbowl),” said Barbara Bruno, faculty specialist at SOEST and co-author of the first article. “The fishbowl — ​not the fish — ​ needs to change.”

“Academia can often be reluctant to change, which is unfortunate as much of the workplace culture can serve as barriers to inclusion in STEM,” said John Burns, lead author of the second article and associate professor at UH Hilo. “We must embrace open-mindedness and be ready to transform the very culture of science in order to enhance diversity. Diverse perspectives and ideas not only foster a healthy work environment but can also serve as our most powerful asset, fueling the drive for new discoveries.”

The variant, located in a mitochondrial microprotein dubbed SHLP2, was found to be highly protective against Parkinson’s disease; individuals with this mutation are half as likely to develop the disease as those who do not carry it. The variant form of the protein is relatively rare and is found primarily in people of European descent.

The findings appear on January 3, 2024, in the journal Molecular Psychiatry.

First discovered by Pinchas Cohen at the USC Leonard Davis School in 2016, SHLP2 is made within the cell’s mitochondria. Previous research from the Cohen Lab established that SHLP2 is associated with protection from aging-related diseases including cancer and that levels of the microprotein change in patients with Parkinson’s disease; they rise as the body attempts to counteract the pathology of Parkinson’s disease but often fail to mount additional production as the disease progresses.

This latest finding builds upon the USC team’s prior mitochondrial research and represents an advance at the intersection of longevity science, precision health, and microprotein discovery.

“This study advances our understanding of why people might get Parkinson’s and how we might develop new therapies for this devastating disease,” said Cohen, professor of gerontology, medicine and biological sciences and senior author of the study. “Also, because most research is done on well-established protein-coding genes in the nucleus, it underscores the relevance of exploring mitochondrial-derived microproteins as a new approach to the prevention and treatment of diseases of aging.”

For this study, first author Su-Jeong Kim, an adjunct research assistant professor of gerontology at the USC Leonard Davis School, led a series of experiments that leveraged the Lab-developed microprotein discovery pipeline that begins with a big data-driven analysis to identify variants involved in disease. Thousands of human study subjects from the Health & Retirement Study, Cardiovascular Health Study, and Framingham Heart Study were screened for the SHLP2 variant. By comparing genetic variants in the mitochondrial DNA in patients with Parkinson’s disease and in controls, researchers found a highly protective variant found in 1% of Europeans, that reduced risk of Parkinson’s disease by twofold, to 50% of average.

Next, they demonstrated that this naturally occurring variant results in a change to the amino acid sequence and protein structure of SHLP2. The mutation — a single nucleotide polymorphism (SNP), or a change to a single letter of the protein’s genetic code — is essentially a “gain-of-function” variant that is associated with higher expression of SHLP2 and also makes the microprotein more stable. According to their findings, the SHLP2 variant has high stability compared to the more common type and provides enhanced protection against mitochondrial dysfunction.

The research team was able to use targeted mass spectrometry techniques to identify the tiny peptide’s presence in neurons and found that SHLP2 specifically binds to an enzyme in mitochondria called mitochondrial complex 1. This enzyme is essential for life, and declines in its function have been linked not only to Parkinson’s disease but also to strokes and heart attacks.

The increased stability of the SHLP2 variant means that the microprotein binds to mitochondrial complex 1 more stably, prevents the decline of the enzyme’s activity, and thus reduces mitochondrial dysfunction. The benefits of the mutant form of SHLP2 were observed in both in vitro experiments in human tissue samples as well as in mouse models of Parkinson’s disease, according to the study.

“Our data highlights the biological effects of a particular gene variant and the potential molecular mechanisms by which this mutation may reduce the risk for Parkinson’s disease,” said Kim. “These findings may guide the development of therapies and provide a roadmap for understanding other mutations found in mitochondrial microproteins.”

Coauthors included Brendan Miller, Nicolas G. Hartel, Ricardo Ramirez II, Regina Gonzalez Braniff, Naphada Leelaprachakul, Amy Huang, Yuzhu Wang, Thalida Em Arpawong, Eileen M. Crimmins, Kelvin Yen, Giselle M. Petzinger, Michael W. Jakowec, and Nicholas A. Graham of USC; Penglong Wang and Chunyu Liu of the National Heart, Lung, and Blood Institute, National Institutes of Health; and Xianbang Sun and Daniel Levy of Boston University.

This work was supported by Department of Defense grant W81XWH2110625 to Kim and by NIH grants P01AG034906, R01AG068405 and P30AG068345 to Cohen. Pinchas Cohen is a consultant of CohBar Inc.