From Penn Today : “Evolutionary ‘arms race’ may help keep cell division honest”

From Penn Today

at

U Penn bloc

University of Pennsylvania

August 24, 2021
Katherine Unger Baillie

Research from the lab of Michael Lampson in the School of Arts & Sciences suggests that certain proteins may have evolved to reduce the likelihood of chromosomes ‘cheating’ to bias their chance of winding up in an egg during the cell-division process meiosis.

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Normally, we think each copy of our 23 chromosomes has a 50-50 shot of getting in our reproductive cells—eggs and sperm—but that’s not the case. In a new study Penn biologists show how proteins have evolved to suppress cheating chromosomes and keep the odds close to even. Image: Jun Ma.

Eggs and sperm are special cells for many reasons, but one of the characteristics that sets them apart is that, unlike other human cells which have two copies of 23 chromosomes, one from the mother and one from the father, these sex cells or gametes, have only one.

Previous research, led by Michael Lampson of Penn’s School of Arts & Sciences, has shown that these chromosomes don’t get passed on to gametes by chance; certain factors can tip the scales, making it more likely that one of the two copies will be passed to the next generation.

In a new paper, Lampson and colleagues uncover a force at work to balance the scales during meiosis-the cell-division process that gives rise to gametes, bringing the odds closer to 50-50 that a particular chromosome will get into a viable egg.

The work, published in the journal Cell, finds that, while a mechanism exists to give certain chromosomes the upper hand during meiosis, a separate, parallel pathway acts to suppress that advantage. Proteins that act in the two pathways appear to be in an evolutionary arms race, the researchers say, potentially to avoid the possibility of biased chromosome inheritance leading to mistakes and abnormalities in eggs, such as aneuploidy, or having an abnormal number of chromosomes, which can result in birth defects.

“If we think of these chromosomes that are getting in the egg as being selfish, selfish implies that they’re maximizing their own transmission at some cost to the organism overall,” says Lampson. “If there is a cost, then there might be other genes under pressure to suppress the selfish ones or suppress that cost.”

The current work aimed to look for that suppressive pathway, building on a 2017 paper in Science in which Lampson and members of his lab laid out the mechanism by which an asymmetry arises in the meiotic spindle, a structure composed of microtubules that pulls chromosomes to opposite sides of a cell prior to division. This asymmetry led to biases in chromosome transmission. They found that “selfish” centromeres, the part of the chromosome that attaches to the spindle, were more likely than “unselfish” centromeres to be able to detach and reattach to the side of the cell that was destined to become a viable egg rather than the polar body, which is typically degraded.

Then, in a 2019 paper in Cell, the researchers laid out more details of the process. They found that the selfish centromeres were able to bias transmission by recruiting certain proteins that destabilized attachment to the spindle, again increasing the chance of ending up in the egg rather than the polar body. These proteins played a role in enabling the centromeres’ detachment from the spindle.

“We had gained this understanding of how selfishness works,” Lampson says, so in the new paper, “we wanted to understand how suppression works.”

Earlier research had shown that some of the proteins acting on the centromere were evolving rapidly in various animal species. Lampson and colleagues hypothesized that this rapid evolution could be evidence of an “arms race” between selfish and suppressive factors, akin to what is seen in the immune system, which can quickly evolve to respond to changing threats from pathogens.

“It was surprising to find a whole bunch of rapidly evolving proteins functioning at the centromere because you would probably expect those to be highly conserved because they’re so important in cell division,” Lampson says. “But it’s a signature of the arms race, just like we see in the immune system: If selfish centromeres are going to cheat, there are likely proteins evolving to tamp down that suppression.”

The researchers already knew that effector proteins that bias chromosome transmission were recruited to the centromere by a route known as the kinetochore pathway. To find a suppressive pathway, they looked to heterochromatin-tightly-packed DNA which is also known to recruit proteins to the centromere. To test whether the heterochromatin pathway might be balancing out the biasing effect of the kinetochore pathway, the researchers selectively modified an enzyme that acted in each pathway.

When they modified the protein CENP-C, disrupting the kinetochore pathway, they observed the bias between selfish and unselfish centromere decline, with chromosomes lining up more symmetrically in the cell prior to the completion of meiosis. In contrast, when they deleted the protein CENP-B, which is involved in recruiting proteins in the heterochromatin pathway, the asymmetry in the chromosomes became more pronounced, with selfish centromeres permitted to bias chromosome transmission to the egg.

“There seem to be these subtle changes at work,” Lampson says, “because both of these pathways are essential. You can’t kill the kinetochore pathway because it’s fundamental for cell division, but at the same time you want to reduce the opportunity for centromeres to be selfish. So evolution seems to be acting to respond to these simultaneous pressures.”

The findings illuminate the evolutionary battlefield present in our own bodies, Lampson says. “I think it’s really interesting that there are these selfish components of our own genomes that have essential roles. These very, very fundamental aspects of our cell biology actually reflect competing pressures.”

He and colleagues hope to continue to explore in follow-up work whether the potential costs of selfish factors can result in impactful mistakes in gamete production or other problems in meiosis. “Females don’t make very many eggs,” Lampson says, “so you would think each one would be precious, and we don’t want to make any mistakes. But mistakes sometimes occur; sometimes too many chromosomes get in. So, are mistakes somehow related to these selfish factors?”

See the full article here .

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Academic life at University of Pennsylvania (US) is unparalleled, with 100 countries and every U.S. state represented in one of the Ivy League’s most diverse student bodies. Consistently ranked among the top 10 universities in the country, Penn enrolls 10,000 undergraduate students and welcomes an additional 10,000 students to our world-renowned graduate and professional schools.

Penn’s award-winning educators and scholars encourage students to pursue inquiry and discovery, follow their passions, and address the world’s most challenging problems through an interdisciplinary approach.

The University of Pennsylvania(US) is a private Ivy League research university in Philadelphia, Pennsylvania. The university claims a founding date of 1740 and is one of the nine colonial colleges chartered prior to the U.S. Declaration of Independence. Benjamin Franklin, Penn’s founder and first president, advocated an educational program that trained leaders in commerce, government, and public service, similar to a modern liberal arts curriculum.

Penn has four undergraduate schools as well as twelve graduate and professional schools. Schools enrolling undergraduates include the College of Arts and Sciences; the School of Engineering and Applied Science; the Wharton School; and the School of Nursing. Penn’s “One University Policy” allows students to enroll in classes in any of Penn’s twelve schools. Among its highly ranked graduate and professional schools are a law school whose first professor wrote the first draft of the United States Constitution, the first school of medicine in North America (Perelman School of Medicine, 1765), and the first collegiate business school (Wharton School, 1881).

Penn is also home to the first “student union” building and organization (Houston Hall, 1896), the first Catholic student club in North America (Newman Center, 1893), the first double-decker college football stadium (Franklin Field, 1924 when second deck was constructed), and Morris Arboretum, the official arboretum of the Commonwealth of Pennsylvania. The first general-purpose electronic computer (ENIAC) was developed at Penn and formally dedicated in 1946. In 2019, the university had an endowment of $14.65 billion, the sixth-largest endowment of all universities in the United States, as well as a research budget of $1.02 billion. The university’s athletics program, the Quakers, fields varsity teams in 33 sports as a member of the NCAA Division I Ivy League conference.

As of 2018, distinguished alumni and/or Trustees include three U.S. Supreme Court justices; 32 U.S. senators; 46 U.S. governors; 163 members of the U.S. House of Representatives; eight signers of the Declaration of Independence and seven signers of the U.S. Constitution (four of whom signed both representing two-thirds of the six people who signed both); 24 members of the Continental Congress; 14 foreign heads of state and two presidents of the United States, including Donald Trump. As of October 2019, 36 Nobel laureates; 80 members of the American Academy of Arts and Sciences(US); 64 billionaires; 29 Rhodes Scholars; 15 Marshall Scholars and 16 Pulitzer Prize winners have been affiliated with the university.

History

The University of Pennsylvania considers itself the fourth-oldest institution of higher education in the United States, though this is contested by Princeton University(US) and Columbia(US) Universities. The university also considers itself as the first university in the United States with both undergraduate and graduate studies.

In 1740, a group of Philadelphians joined together to erect a great preaching hall for the traveling evangelist George Whitefield, who toured the American colonies delivering open-air sermons. The building was designed and built by Edmund Woolley and was the largest building in the city at the time, drawing thousands of people the first time it was preached in. It was initially planned to serve as a charity school as well, but a lack of funds forced plans for the chapel and school to be suspended. According to Franklin’s autobiography, it was in 1743 when he first had the idea to establish an academy, “thinking the Rev. Richard Peters a fit person to superintend such an institution”. However, Peters declined a casual inquiry from Franklin and nothing further was done for another six years. In the fall of 1749, now more eager to create a school to educate future generations, Benjamin Franklin circulated a pamphlet titled Proposals Relating to the Education of Youth in Pensilvania, his vision for what he called a “Public Academy of Philadelphia”. Unlike the other colonial colleges that existed in 1749—Harvard University(US), William & Mary(US), Yale Unversity(US), and The College of New Jersey(US)—Franklin’s new school would not focus merely on education for the clergy. He advocated an innovative concept of higher education, one which would teach both the ornamental knowledge of the arts and the practical skills necessary for making a living and doing public service. The proposed program of study could have become the nation’s first modern liberal arts curriculum, although it was never implemented because Anglican priest William Smith (1727-1803), who became the first provost, and other trustees strongly preferred the traditional curriculum.

Franklin assembled a board of trustees from among the leading citizens of Philadelphia, the first such non-sectarian board in America. At the first meeting of the 24 members of the board of trustees on November 13, 1749, the issue of where to locate the school was a prime concern. Although a lot across Sixth Street from the old Pennsylvania State House (later renamed and famously known since 1776 as “Independence Hall”), was offered without cost by James Logan, its owner, the trustees realized that the building erected in 1740, which was still vacant, would be an even better site. The original sponsors of the dormant building still owed considerable construction debts and asked Franklin’s group to assume their debts and, accordingly, their inactive trusts. On February 1, 1750, the new board took over the building and trusts of the old board. On August 13, 1751, the “Academy of Philadelphia”, using the great hall at 4th and Arch Streets, took in its first secondary students. A charity school also was chartered on July 13, 1753 by the intentions of the original “New Building” donors, although it lasted only a few years. On June 16, 1755, the “College of Philadelphia” was chartered, paving the way for the addition of undergraduate instruction. All three schools shared the same board of trustees and were considered to be part of the same institution. The first commencement exercises were held on May 17, 1757.

The institution of higher learning was known as the College of Philadelphia from 1755 to 1779. In 1779, not trusting then-provost the Reverend William Smith’s “Loyalist” tendencies, the revolutionary State Legislature created a University of the State of Pennsylvania. The result was a schism, with Smith continuing to operate an attenuated version of the College of Philadelphia. In 1791, the legislature issued a new charter, merging the two institutions into a new University of Pennsylvania with twelve men from each institution on the new board of trustees.

Penn has three claims to being the first university in the United States, according to university archives director Mark Frazier Lloyd: the 1765 founding of the first medical school in America made Penn the first institution to offer both “undergraduate” and professional education; the 1779 charter made it the first American institution of higher learning to take the name of “University”; and existing colleges were established as seminaries (although, as detailed earlier, Penn adopted a traditional seminary curriculum as well).

After being located in downtown Philadelphia for more than a century, the campus was moved across the Schuylkill River to property purchased from the Blockley Almshouse in West Philadelphia in 1872, where it has since remained in an area now known as University City. Although Penn began operating as an academy or secondary school in 1751 and obtained its collegiate charter in 1755, it initially designated 1750 as its founding date; this is the year that appears on the first iteration of the university seal. Sometime later in its early history, Penn began to consider 1749 as its founding date and this year was referenced for over a century, including at the centennial celebration in 1849. In 1899, the board of trustees voted to adjust the founding date earlier again, this time to 1740, the date of “the creation of the earliest of the many educational trusts the University has taken upon itself”. The board of trustees voted in response to a three-year campaign by Penn’s General Alumni Society to retroactively revise the university’s founding date to appear older than Princeton University, which had been chartered in 1746.

Research, innovations and discoveries

Penn is classified as an “R1” doctoral university: “Highest research activity.” Its economic impact on the Commonwealth of Pennsylvania for 2015 amounted to $14.3 billion. Penn’s research expenditures in the 2018 fiscal year were $1.442 billion, the fourth largest in the U.S. In fiscal year 2019 Penn received $582.3 million in funding from the National Institutes of Health(US).

In line with its well-known interdisciplinary tradition, Penn’s research centers often span two or more disciplines. In the 2010–2011 academic year alone, five interdisciplinary research centers were created or substantially expanded; these include the Center for Health-care Financing; the Center for Global Women’s Health at the Nursing School; the $13 million Morris Arboretum’s Horticulture Center; the $15 million Jay H. Baker Retailing Center at Wharton; and the $13 million Translational Research Center at Penn Medicine. With these additions, Penn now counts 165 research centers hosting a research community of over 4,300 faculty and over 1,100 postdoctoral fellows, 5,500 academic support staff and graduate student trainees. To further assist the advancement of interdisciplinary research President Amy Gutmann established the “Penn Integrates Knowledge” title awarded to selected Penn professors “whose research and teaching exemplify the integration of knowledge”. These professors hold endowed professorships and joint appointments between Penn’s schools.

Penn is also among the most prolific producers of doctoral students. With 487 PhDs awarded in 2009, Penn ranks third in the Ivy League, only behind Columbia University(US) and Cornell University(US) (Harvard University(US) did not report data). It also has one of the highest numbers of post-doctoral appointees (933 in number for 2004–2007), ranking third in the Ivy League (behind Harvard and Yale University(US)) and tenth nationally.

In most disciplines Penn professors’ productivity is among the highest in the nation and first in the fields of epidemiology, business, communication studies, comparative literature, languages, information science, criminal justice and criminology, social sciences and sociology. According to the National Research Council nearly three-quarters of Penn’s 41 assessed programs were placed in ranges including the top 10 rankings in their fields, with more than half of these in ranges including the top five rankings in these fields.

Penn’s research tradition has historically been complemented by innovations that shaped higher education. In addition to establishing the first medical school; the first university teaching hospital; the first business school; and the first student union Penn was also the cradle of other significant developments. In 1852, Penn Law was the first law school in the nation to publish a law journal still in existence (then called The American Law Register, now the Penn Law Review, one of the most cited law journals in the world). Under the deanship of William Draper Lewis, the law school was also one of the first schools to emphasize legal teaching by full-time professors instead of practitioners, a system that is still followed today. The Wharton School was home to several pioneering developments in business education. It established the first research center in a business school in 1921 and the first center for entrepreneurship center in 1973 and it regularly introduced novel curricula for which BusinessWeek wrote, “Wharton is on the crest of a wave of reinvention and change in management education”.

Several major scientific discoveries have also taken place at Penn. The university is probably best known as the place where the first general-purpose electronic computer (ENIAC) was born in 1946 at the Moore School of Electrical Engineering.

ENIAC UPenn

It was here also where the world’s first spelling and grammar checkers were created, as well as the popular COBOL programming language. Penn can also boast some of the most important discoveries in the field of medicine. The dialysis machine used as an artificial replacement for lost kidney function was conceived and devised out of a pressure cooker by William Inouye while he was still a student at Penn Med; the Rubella and Hepatitis B vaccines were developed at Penn; the discovery of cancer’s link with genes; cognitive therapy; Retin-A (the cream used to treat acne), Resistin; the Philadelphia gene (linked to chronic myelogenous leukemia) and the technology behind PET Scans were all discovered by Penn Med researchers. More recent gene research has led to the discovery of the genes for fragile X syndrome, the most common form of inherited mental retardation; spinal and bulbar muscular atrophy, a disorder marked by progressive muscle wasting; and Charcot–Marie–Tooth disease, a progressive neurodegenerative disease that affects the hands, feet and limbs.

Conductive polymer was also developed at Penn by Alan J. Heeger, Alan MacDiarmid and Hideki Shirakawa, an invention that earned them the Nobel Prize in Chemistry. On faculty since 1965, Ralph L. Brinster developed the scientific basis for in vitro fertilization and the transgenic mouse at Penn and was awarded the National Medal of Science in 2010. The theory of superconductivity was also partly developed at Penn, by then-faculty member John Robert Schrieffer (along with John Bardeen and Leon Cooper). The university has also contributed major advancements in the fields of economics and management. Among the many discoveries are conjoint analysis, widely used as a predictive tool especially in market research; Simon Kuznets’s method of measuring Gross National Product; the Penn effect (the observation that consumer price levels in richer countries are systematically higher than in poorer ones) and the “Wharton Model” developed by Nobel-laureate Lawrence Klein to measure and forecast economic activity. The idea behind Health Maintenance Organizations also belonged to Penn professor Robert Eilers, who put it into practice during then-President Nixon’s health reform in the 1970s.

International partnerships

Students can study abroad for a semester or a year at partner institutions such as the London School of Economics(UK), University of Barcelona [Universitat de Barcelona](ES), Paris Institute of Political Studies [Institut d’études politiques de Paris](FR), University of Queensland(AU), University College London(UK), King’s College London(UK), Hebrew University of Jerusalem(IL) and University of Warwick(UK).