Human Genome Was Shaped by an Evolutionary Arms Race with Itself

New study of primate genomes reveals an ongoing battle to control 'jumping genes,' driving the evolution of greater genomic complexity

Sunday, 28 September 2014

New findings by scientists at the University of California, Santa Cruz, suggest that an evolutionary arms race between rival elements within the genomes of primates drove the evolution of complex regulatory networks that orchestrate the activity of genes in every cell of our bodies.

The arms race is between mobile DNA sequences known as "retrotransposons" (a.k.a. "jumping genes") and the genes that have evolved to control them. The UC Santa Cruz researchers have, for the first time, identified genes in humans that make repressor proteins to shut down specific jumping genes. The researchers also traced the rapid evolution of the repressor genes in the primate lineage.

Their findings, published September 28 in Nature, show that over evolutionary time, primate genomes have undergone repeated episodes in which mutations in jumping genes allowed them to escape repression, which drove the evolution of new repressor genes, and so on. Furthermore, their findings suggest that repressor genes that originally evolved to shut down jumping genes have since come to play other regulatory roles in the genome.

"We have basically the same 20,000 protein-coding genes as a frog, yet our genome is much more complicated, with more layers of gene regulation. This study helps explain how that came about," said Sofie Salama, a research associate at the UC Santa Cruz Genomics Institute who led the study.

Retrotransposons are thought to be remnants of ancient viruses that infected early animals and inserted their genes into the genome long before humans evolved. Now they can only replicate themselves within the genome. Depending on where a new copy gets inserted into the genome, a jumping event can disrupt normal genes and cause disease. Often the effect is neutral, simply adding to the overall size of the genome. Very rarely the effect might be advantageous, because the added DNA can itself be a source of new regulatory elements that enhance gene expression. But the high probability of deleterious effects means natural selection favours the evolution of mechanisms to prevent jumping events.

Scientists estimate that jumping genes or "transposable elements" account for at least 50 percent of the human genome, and retrotransposons are by far the most common type.

"There have been successive waves of retrotransposon activity in primate evolution, when a transposable element changed to become expressed and replicated itself throughout the genome until something turned it off," Salama said.

"We've discovered a major mechanism by which the genome is able to shut down these mobile DNA elements."

The repressors identified in the new study belong to a large family of proteins known as "KRAB zinc finger proteins." These are DNA-binding proteins that repress gene activity, and they constitute the largest family of gene-regulating proteins in mammals. The human genome has over 400 genes for KRAB zinc finger proteins, and about 170 of them have emerged since primates diverged from other mammals.

According to Salama, her team's findings support the idea that expansion of this family of repressor genes occurred in response to waves of retrotransposon activity. Because repression of a jumping gene also affects genes located near it on the chromosome, the researchers suspect that these repressors have been co-opted for other gene-regulatory functions, and that those other functions have persisted and evolved long after the jumping genes the repressors originally turned off have degraded due to the accumulation of random mutations.

"The way this type of repressor works, part of it binds to a specific DNA sequence and part of it binds other proteins to recruit a whole complex of proteins that creates a repressive landscape in the genome. This affects other nearby genes, so now you have a potential new layer of regulation available for further evolution," Salama said.

KRAB zinc finger proteins are the subject of intensive research as scientists try to sort out their many regulatory roles within the genome. The idea that they are involved in repression of jumping genes is not new – previous studies by other researchers have shown that these proteins silence jumping genes in mouse embryonic stem cells. But until now, no one had been able to demonstrate that the same thing occurs in human cells.

The UC Santa Cruz team developed a novel assay to test whether a particular KRAB zinc finger protein could shut down certain jumping genes. The first authors of the paper, postdoctoral researcher Frank Jacobs and graduate student David Greenberg, came up with the strategy of testing primate retrotransposons in non-primate cells by using mouse embryonic stem cells that contain a single human chromosome. In the environment of a mouse cell, jumping genes that were repressed in primate cells became active. Greenberg then developed an assay for testing individual zinc finger proteins for their ability to turn off a primate jumping gene in the mouse cell environment.

"We did all our tests in mouse cells because they lack all of the primate zinc finger proteins, so when you put primate retrotransposons into a mouse cell they're all active," Salama explained.

The results demonstrated that two human proteins called ZNF91 and ZNF93 bind and repress two major classes of retrotransposons (known as SVA and L1PA) that are currently or recently active in primates. Assistant research scientist Benedict Paten directed graduate student Ngan Nguyen in a painstaking analysis of primate genomes, including the reconstruction of ancestral genomes, which showed that ZNF91 underwent structural changes 8 to 12 million years ago that enabled it to repress SVA elements.

Experiments with ZNF 93, which shuts down L1PA retrotransposons, provided a striking illustration of the arms race between jumping genes and repressors. The researchers found that, while it is good at shutting down many L1PA elements, there is one subset of a recently evolved lineage of L1PA that has lost a short section of DNA that includes the ZNF93 binding site. Without the binding site, these jumping genes evade repression by ZNF93. Interestingly, when the researchers put the missing sequence back into one of these genes and put it in a mouse cell without ZNF93, they found that it was better at jumping. So even though the sequence helps with jumping activity, losing it gives the jumping gene an advantage in primates by allowing it to escape repression by ZNF93.

"That's kind of the icing on the cake for aficionados of molecular evolution, because it demonstrates that this is a never-ending race," Salama said.

"KRAB zinc finger proteins are a rare class of proteins that is rapidly expanding and evolving in mammalian genomes, which makes sense because the transposable elements are themselves continually evolving to escape repression."

Corresponding author David Haussler, professor of biomolecular engineering and director of the UC Santa Cruz Genomics Institute, said the study involved close collaboration between his group's "wet lab," directed by Salama, and the "dry lab" where researchers under Paten's direction used the computational tools of genome bioinformatics to reconstruct the evolutionary history of primate genomes. Haussler, a Howard Hughes Medical Institute investigator who has used his background in computer science to do pioneering work in genomics, said he established the wet lab to enable just this kind of collaboration.

"Both parts were integral to this study, and there was a lot of back and forth between them. This paper shows how important it is to integrate computational and experimental approaches to fundamental scientific problems, such as how and why we continuously evolve to be more complex," Haussler said.

Source: University of California - Santa Cruz

Contact: Tim Stephens

Reference:

An evolutionary arms race between KRAB zinc-finger genes ZNF91/93 and SVA/L1 retrotransposons

Frank M. J. Jacobs, David Greenberg, Ngan Nguyen, Maximilian Haeussler, Adam D. Ewing, Sol Katzman, Benedict Paten, Sofie R. Salama & David Haussler

Nature, 28 September  2014, doi:10.1038/nature13760

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Parents Give Kids Fewer Gene Mutations Than Was Thought

Landmark study is first to look at genome of all family members Thursday, 11 March 2010 Researchers at the University of Utah Health Sciences and other institutions have sequenced for the first time the entire genome of a family, enabling them to accurately estimate the average rate at which parents pass genetic mutations to their offspring and also identify precise locations where parental chromosomes exchange information that creates new combinations of genetic traits in their children. Led by scientists at the Seattle-based Institute for Systems Biology, the study, published Thursday, March 11, 2010 in Science Express, sequenced the entire genome of a family of four — the parents, daughter, and son. By comparing the parents' DNA sequences to those of their children, the researchers estimated with a high degree of certainty that each parent passes 30 mutations — for a total of 60 — to their offspring. Scientists long had estimated that each parent passes 75 gene mutations to their children. "That's the kind of power you get from looking at the whole genome," said Lynn B. Jorde, Ph.D., professor and chair of the Department of Human Genetics at the University of Utah School of Medicine. "The mutation rate was less than half of what we'd thought." "An important finding is that by determining the genome sequences of an entire family one can identify many DNA sequencing errors, and thus greatly increase the accuracy of the data," said Leroy Hood, MD, PhD, the paper's other corresponding author, and co-founder and president of Institute for Systems Biology. "This will ultimately help us understand the role of genetic variations in the diagnosis, treatment, and prevention of disease." Genetic Clock Most mutations, as far as medical researchers know, have no consequence for a child's health. But knowing the rate at which parents send on mutations to their offspring is critical information, according to Jorde. "The mutation rate is our clock, and every time it ticks we have a new genetic variant," he said. "We need to know how fast the clock ticks." Everybody has about 22,000 genes, which contain the genetic blueprint for human life. This blueprint, called DNA, comprises more than 3 billion "base pairs" that determine genetic makeup. In1990, scientists worldwide began assembling the entire sequence of base pairs in all 22,000 human genes, a process called sequencing. When they completed the project in 2003, the scientists had put together the complete picture of the proper sequence of base pairs in the human genome. When Jorde and the Science study's senior author, David J. Galas, Ph.D., of the Institute of Systems Biology, were discussing the idea of sequencing the genome of an entire family, they decided to look for one with known genetic disorders. A family of four turned out to be right for the study. Although the parents had no genetic abnormalities, they each carried recessive genes that resulted in their son and daughter being born with two extremely rare conditions – Miller's syndrome and Primary Ciliary Dyskinesia (PCD). Miller's syndrome, a disorder characterized by facial and limb malformations, is thought to occur in perhaps one in 1 million people and has been diagnosed in only two families in the world, along with a few sporadic other cases. PCD is a condition in which the tiny hair-like structures that are supposed to move mucus out of airways in the lungs do not function. The chances of having PCD are estimated at one in 10,000. The odds of someone having both PCD and Miller's syndrome are less than one in 10 billion, according to Jorde. By comparing the variants in the children's DNA sequences with the Human Genome Project and other public databases, the researchers confirmed an earlier study that identified four candidate gene mutations for causing each disorder. Gene Mutation Rate Genetic mutations are passed to offspring when base pairs of DNA are altered in the genome. A Mountain View, Calif., company, Complete Genomics, used new, high-powered technology to sequence the genomes of each family member. Then, using the DNA sequence established by the Human Genome Project as a reference, Chad D. Huff, Ph.D., a post-doctoral fellow in Jorde's lab and co-first author on the study, compared the family's DNA base pair sequences to those established by the Human Genome Project. "Comparing the family's sequences to the Human Genome Project allowed us to screen out potential errors in the DNA sequencing process," Jorde said. "To estimate the mutation rate, we compared the parents' sequences with those of their children. Differences in the sequences that were not caused by sequencing errors were caused by mutations." From this, Huff estimated the number of gene mutations each parent gives their child. This rate probably will vary, according to Jorde, depending on how old the parents are, particularly the father, when they reproduce. To find the locations where parental chromosomes exchange genetic information, which are called crossover sites, the researchers compared variations in the parents' DNA sequences to their children's, looking for blocks of DNA that the son and daughter inherited intact from the parents. When they found blocks that were interrupted, the researchers concluded they had identified the crossover sites. "We found that 60 percent of the crossovers take place in specific hotspots on the chromosomes," Jorde said. "We were able to locate these sites right down to the base pairs." "This estimate could have implications for how we think about genetic diversity, but more importantly the approach has the potential to increase enormously the power and impact of genetic research," said Galas. "Our study illustrates the beginning of a new era in which the analysis of a family's genome can aid in the diagnosis and treatment of individual family members. We could soon find that our family's genome sequence will become a normal part of our medical records." Future Studies The study opens the door for numerous other investigations in the future. Jorde expects researchers will use family sequence analysis to begin narrowing down the genetic causes of more common diseases. Moreover, as the cost of genome sequencing continues to drop — the Human Genome Project cost about $3 billion, and now individuals can get their genome sequenced for $5,000 to $10,000 — it will be an important part of individual medical records, the researchers believe. "We would predict that the information derived from family genomes, along with relevant environmental and medical information, will constitute the medical records of the future," the study concludes. Reference: Analysis of Genetic Inheritance in a Family Quartet by Whole-Genome Sequencing Jared C. Roach, Gustavo Glusman, Arian F. A. Smit, Chad D. Huff, Robert Hubley, Paul T. Shannon, Lee Rowen, Krishna P. Pant, Nathan Goodman, Michael Bamshad, Jay Shendure, Radoje Drmanac, Lynn B. Jorde, Leroy Hood, and David J. Galas Science, published online March 10 2010; DOI 10.1126/science.1186802 ......... ZenMaster

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Genetic Recombination gets More Precise

Scientists generate the most precise map of genetic recombination ever Friday, 11 July 2008 Genetic recombination, the process by which sexually reproducing organisms shuffle their genetic material when producing germ cells, leads to offspring with a new genetic make-up and influences the course of evolution. In the current issue of Nature, researchers at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, and the EMBL-European Bioinformatics Institute (EMBL-EBI) in Hinxton, UK, present the most precise map of genetic recombination yet. The study sheds light on fundamental questions about genetic shuffling and has implications for the tracking of disease genes and their inheritance. In order to generate germ cells, sexually reproducing organisms undergo a complex series of cell divisions (meiosis) that includes the shuffling of genetic material inherited from the two parents. Equivalent chromosomes from mother and father pair up and exchange sections of DNA in a process called crossover. In a different type of recombination, called non-crossover, a small piece of DNA is copied from one chromosome onto the other without reciprocal exchange leading to gene conversion. Non-crossovers are minute events with a subtler effect than the exchange of larger fragments, but both types of recombination can increase genetic diversity and explain why organisms of the same species differ in many ways. Both types of recombination can also act to separate the transmission of neighbouring genes, which are normally inherited together. The groups of Lars Steinmetz at EMBL and Wolfgang Huber at EMBL-EBI have produced the most detailed map to date of recombination events in the yeast genome. "Our map has the highest resolution of recombination events that currently exists for any organism. We can locate crossovers and even hard-to-trace non-crossovers, typically with a precision of about 80 bases. This resolution is 20 times higher than in any existing yeast map and more than 360 times higher than a recent human map," says Steinmetz. The map revealed many new insights into the organisation of recombination in yeast. On average over 150 recombination events were observed during a typical meiosis. These events did not occur uniformly across the genome. The recombination rate varied according to location, with events concentrated at so-called hotspots, some of which favoured either crossovers or non-crossovers. The researchers also found evidence for interference between crossovers and non-crossovers - a phenomenon previously only known to occur between crossovers - that makes it unlikely for two recombination events to happen in close proximity. The fundamental principles of recombination are likely to be shared between yeast and humans. "Our map expands our understanding of crossover and provides a wealth of new information about non-crossovers and gene conversion. It will act as a reference for future research into recombination," says Richard Bourgon from Huber's group, who developed the statistical methodology for this new type of data. The insights gained will not only help tackle questions about the basic mechanisms of recombination; they will also have practical implications for the tracking of disease genes in humans. Reference: High-resolution mapping of meiotic crossovers and non-crossovers in yeast Eugenio Mancera, Richard Bourgon, Alessandro Brozzi, Wolfgang Huber & Lars M. Steinmetz Nature advance online publication 9 July 2008 doi:10.1038/nature07135 ......... ZenMaster

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Location matters, even for genes

Location matters, even for genes Wednesday, 13 February 2008 Moving an active gene from the interior of the nucleus to its periphery can inactivate that gene report scientists from the University of Chicago Medical Center in an article to be published early online Feb.13, 2008, in the journal Nature. Attachment to the inner nuclear membrane, they show, can silence genes, preventing their transcription — a novel form of gene regulation. "Several years ago, we and others described the correlation between nuclear positioning and gene activation," said study author Harinder Singh, Louis Block Professor of Molecular Genetics and Cell Biology and an Investigator in the Howard Hughes Medical Institute at the University of Chicago. "With that in mind, we wanted to take the next step, to design an experiment that could test causality. Could we move a gene from the center of the nucleus to the periphery, we asked, and then measure the consequences of such repositioning?" In mammalian nuclei, chromatin — a complex of DNA and associated proteins — is organized into structural domains through interactions with distinct nuclear compartments. In this study, the authors developed the molecular tools to take specific genes from these interior compartments, move them to the periphery and attach them to the nuclear membrane — which turned those genes off. Not only were selected "test" genes that served as markers turned off after being attached to the inner nuclear membrane, but also nearby "real" genes. Singh’s laboratory had become interested in studying the role of nuclear positioning in the control of gene activity based on work analyzing immunoglobulin heavy-chain genes. These genes are assembled by DNA recombination and code for proteins that are a crucial part of antibodies, produced in antibody-secreting lymphocytes or B-cells. "In cells that don’t produce antibodies, like fibroblasts or T-cells, these antibody genes are attached to the inner nuclear membrane and are not recombined or expressed," said Singh. On the other hand, antibody genes are actively transcribed and recombined in developing B-cells, and therefore positioned in the nuclear interior, far away from the periphery. Five years ago, Singh and colleagues reported in Science that even in developing B cells, antibody genes start off at the nuclear periphery. As young cells mature and prepare to produce antibodies, however, these genes move to the interior of the nuclei. The exact ways in which positioning at the outer edge of the nucleus prevents gene expression are still unclear. The likely suspects, said Singh, are some of proteins that reside in the inner nuclear membrane. These proteins may be involved in blocking transcription, he said. They accumulate at sites of attachment and come in contact with parts of certain silenced genes. "So we think that these proteins are part of the molecular machinery that is used for positioning genes at the inner nuclear membrane, as well as potentially for repressing them,” he said. In their Nature paper, Singh's team also showed for the first time that this transcriptional repression was dependent on breakdown and reformation of the nuclear membrane during cell division. The reorganizing of chromosomes occurs when cells divide. "This suggests that cell division is used not only to transmit the genetic information into daughter cells and create two equivalent cells," he said, "but it is also an opportunity for cells to reorganize their genomes in 3D space, sequestering parts of the genome at the nuclear periphery and rendering it inaccessible to transcription.” Singh and colleagues are now looking for examples of striking reorganization of the genome separated by one cell division — in which active genes, that will not be active after the cell divides, get pushed away from the interior to the periphery. The lead author, Karen Reddy, a postdoctoral fellow in the Singh laboratory, proposes that, such compartmentalization "implies the existence of DNA segments that encode for ‘nuclear addresses’ acting like a nuclear zip code to direct or predispose genes to associate with specific regions within the nucleus. This could be tremendously important," she said, "for understanding the underlying cause of some diseases that result from mutations in genes encoding inner nuclear membrane proteins." Additional authors of the paper include J.M. Zullo and E. Bertolino of the University of Chicago. Reference: Transcriptional repression mediated by repositioning of genes to the nuclear lamina Nature advance online publication 13 February 2008 doi:10.1038/nature06727 ......... ZenMaster

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Human Genetic Recombination Studied II

Gene variants may help to distribute the work of evolution between men and women Thursday, 31 January 2008 Scientists from deCODE genetics today report the discovery of two common, single-letter variants in the sequence of the human genome (SNPs) that regulate one of the principle motors of evolution. Versions of the two SNPs, located on chromosome 4p16, have a genome-wide impact on the rate of recombination — the reshuffling of the genome that occurs in the formation of eggs and sperm. Recombination is largely responsible for generating human diversity, the novel configurations of the genome that enable the species to adapt and evolve in an ever-changing environment. Yet remarkably, the versions of the SNPs that increase recombination in men decrease it in women, and vice versa. This highly unusual characteristic may enable the variants to help to maintain a fundamental tension crucial for evolutionary success: promoting the generation of significant diversity within a portion of the population but keeping the pace of this change within certain bounds, maintaining it relatively constant overall and so supporting the stability of the genome and the cohesiveness of the species. “This is the latest in a series of landmark papers from deCODE in which we have utilized our unique capabilities in human genetics to elucidate some of the key mechanisms driving human evolution,” said Kari Stefansson, CEO of deCODE. “We are also excited that we can now immediately enable individuals to see if they carry such variants, by folding the findings announced today — and others we expect to publish in the near future — into our deCODEme™ personal genome analysis service.” The deCODE team identified the SNPs through a genome-wide analysis of more than 300,000 SNPs in approximately 20,000 participants in the company’s gene discovery programs. The SNPs, referred to as rs3796619 and rs1670533, are within the RNF212 gene, and are estimated to account for approximately 22% of paternal variability in recombination and 6.5% of maternal variability. Little is known about RNF212, though it is a mammalian homolog of a gene called ZHP-3 known to be crucial for the success of recombination in other organisms. The paper, entitled ‘Sequence Variants in the RNF212 Gene Associate with Genomewide Recombination Rate,’ is published today in the online edition of Science. deCODE has made a number of breakthrough discoveries in the understanding of recombination, fertility and human evolution. In 2002, deCODE published the most detailed recombination map to date of the genome, demonstrating that there are hotspots and coldspots for recombination in all chromosomes, and that these are very different in women and men. This map provided a template for completing the final assembly of the sequence of the human genome. deCODE scientists then showed that recombination rate varies between families and between women; that recombination rate increases with the age of the mother; and that higher recombination rate correlates with fertility, indicating that evolution appears to place a premium on the generation of human diversity. In 2005, deCODE identified a genetic variant that correlates with higher recombination rate, the first genetic variant ever demonstrated to be under positive evolutionary selection in human populations in real time. References for these and all deCODE’s major discoveries can be found at www.decode.com. About deCODE deCODE is a biopharmaceutical company applying its discoveries in human genetics to the development of drugs and diagnostics for common diseases. deCODE is a global leader in gene discovery — our population approach and resources have enabled us to isolate key genes contributing to major public health challenges from cardiovascular disease to cancer, genes that are providing us with drug targets rooted in the basic biology of disease. deCODE is also leveraging its expertise in human genetics and integrated drug discovery and development capabilities to offer innovative products and services in DNA-based diagnostics, bioinformatics, genotyping, structural biology, drug discovery and clinical development. deCODE is delivering on the promise of the new genetics. ......... ZenMaster

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Human Genetic Recombination Studied I

Inherited individual variations influence patterns of gene shuffling Thursday, 31 January 2008 The first large-scale, high-resolution study of human genetic recombination has found remarkably high levels of individual variation in genetic exchange, the process by which parents pass on a mosaic-like mixture of their genes. In an article appearing February 1, 2008, in Science Express, the online version of Science, researchers from the University of Chicago locate nearly 25,000 recombination events that occurred in the transmission of the parental genomes to 364 offspring. The high-resolution of their maps allows them to provide the precise location of where these genetic exchanges occur, and to assess the differences in recombination rates between individuals. "Genetic recombination is a fundamental process, at the core of reproduction and evolution," said study author Graham Coop, PhD, post-doctoral fellow in the Department of Human Genetics at the University of Chicago, "yet we know very little about where it occurs or why there is so much variation among individuals in this important process." "Now," he said, "we know where it occurs. Understanding where it happens provides us with important clues as to how it happens, how it is regulated and what the mechanisms are that control this essential biological phenomenon." Recombination occurs during meiosis, a special kind of cell division that takes place only in the testicles and ovaries. In the process of making sperm or egg cells, the parent-to-be takes the chromosomes inherited from each of his or her parents and reshuffles them, swapping parts of one chromosome for the matching segments of the other version of that same chromosome. The result is a reproductive cell with a mosaic, or patchwork, of genes, about half from each parent, but shuffled together into entirely new combinations. This process leads to offspring having different combinations of genes than their parents and is thought to have many advantages. Errors in this recombination process during the production of sperm or egg cells underlie a variety of chromosomal abnormalities and can cause deletions of regions of the genome, miscarriage, or genetic disorders such as Down syndrome. The research team focused on the Hutterites, a genetically similar population of European immigrants who settled in the Dakotas in the 19th century and have maintained a communal agricultural lifestyle. One member of the research team, Carole Ober, PhD, professor of human genetics and of obstetrics and gynaecology at the University of Chicago, has been working closely with this group for many years on health and inheritance issues. The researchers collected DNA samples from 725 volunteers, representing 82 overlapping nuclear families, most of which included four or more children. These families are part of a larger 1650-person, 13-generation pedigree of the Hutterites in the US. They used 500,000 markers of genetic variation (SNPs) to determine, along each chromosome, whether the genetic material transmitted from the mother (or father) came from the child's maternal (or paternal) grandmother or grandfather. The large number of markers allowed the researchers to map out at high resolution the locations in the genome where ancestry shifts from one grandparent to another, which are known as recombination events. Chromosomes from the mother (not including the X chromosome) averaged around 40 recombination events per gamete. Those from the father had only 26. The authors confirm a previous finding that older mothers have more recombination events in the transmission of their genome to their offspring, while the father's age has no such effect. For both sexes, the majority of crossovers occur at genetic "hotspots," small regions where genetic exchanges are unusually common. Although the overall rate of hotspot use was similar between the two sexes, a subset of hotspots, "seems to be used mainly by one sex of the other," the authors note. Strikingly the pattern of hotspot used varied among individuals, but seemed to be passed on from generation to generation — a heritable difference potentially pointing to differences in the recombination machinery among individuals. The study uncovered "tremendous variation in recombination rates over all genomic scales considered and in particular heritable variation in hotspot use," the authors conclude. Their ongoing efforts to map this variation should offer insights into the "genetic basis of recombination-rate variation and the selective forces governing the evolution of recombination rates." The National Institutes of Health funded the research. Additional authors include Molly Przeworski, Jonathan Pritchard and Xiaoquan Wen of the Department of Human Genetics at the University of Chicago. ......... ZenMaster

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