Unit 9. Human Genetics and Diversity

I am the family face;

Flesh perishes, I live on,

Projecting trait and trace

Through time to times anon,

And leaping from place to place

Over oblivion.

Thomas Hardy

From a drop of water. . . a logician could infer the possibility of an Atlantic or a Niagara without having seen or heard of one or the other. So all life is a great chain, the nature of which is known whenever we are shown a single link of it.

Sir Arthur Conan Doyle A Study in Scarlet

Exercise 1. What do you know about genetics? Explain the following terms in English:

DNA, RNA Nucleic acid Gene Genome Allele Dominant / recessive gene

Ribosome Replication Transcription Translation Processing Splicing

Phenotype Genotype Enhancer Promoter Silencer Terminator

Selective breeding Hybrid Breeding (crossing) Inbreeding Pure line

Exercise 2. Discuss the following questions about genetic diversity of humans:

1. What role does genetic diversity of humans play?

2. What genetic mechanisms control population diversity?

3. To what degree are different ethnic groups genetically different?

Exercise 3. Read the following two texts (Text A and Text B) about current genetic research of population diversity to check your answers in Exercise 2.

Text A. How Our Genomes Control Diversity

Two research efforts have determined DNA recombination mechanisms that underlie population diversity, how it happens and where in the genetic code it occurs

By Nikhil Swaminathan

Two recent discoveries have shed new light on the source of diversity in the human population. In one study, scientists examined patterns in DNA recombination, the process by which a person's genome is consolidated into one set of chromosomes to pass onto an offspring. In the other, a link was made between variants of a particular gene and the extent to which DNA recombination occurs.

In human testes and ovaries, where sperm cells and egg cells, respectively, are manufactured, sections of chromosomes inherited from a person's parents are shuffled together to create a collage of genetic material that is passed to offspring. This process by which a new, unique set of chromosomes is created (with a mix of roughly half the material coming from each parent) is called DNA recombination and is the source of variation in populations. "Recombination impacts population diversity," says George Coop, a postdoctoral fellow in human genetics at the University of Chicago and co-author of an article that details variation in the pattern in which genes are shuffled from individual to individual. "Recombination is the way that you generate novel haplotypes, novel combinations of mutations." (Haplotypes are combinations of different versions of genes on a single chromosome that are inherited as a unit.)

Coop and colleagues in Science reveal the results of a high-resolution study designed to map the locations where recombination occurs—where one parent's genes have been swapped out for another. Using a population of 725 Hutterites—communal farmers who settled in the Dakotas and Montana in the mid-19th century—the team scanned genomes for 500,000 single-nucleotide polymorphisms (SNPs). SNPs mark points of genetic variation to estimate where DNA shuffles occurred. Researchers can tell which part of a child's genetic code came from which of its four grandparents by comparing variants in both.

The researchers noted nearly 25,000 total recombination events in analyses of 364 offspring. Excluding the sex chromosomes, the team found that eggs typically showed 40 instances of recombination on each of their chromosomes, whereas the chromosomes in sperm are typically made with 26 recombinational occurrences. The University of Chicago team also noted that as women age, more recombination takes place during meiosis (the cellular process that produces an egg). In men, there is no age effect. Further, they noted that such incidents tended to focus on so-called "hot spots," locations where this crossover takes place often. Some turned out to be gender specific, with females utilizing some recombination regions more often than males (and vice versa). The usage of these zones of frequent recombination varied between individuals, but it seemed to be conserved among families, indicating that the extent and pattern of recombination may be inherited.

Interestingly, a finding out of the Icelandic biotech firm deCODE genetics, also appearing in Science, sheds light on that last observation. From a genome-wide analysis looking at 300,000 SNPs in 20,000 people, deCODE scientists were able to find two locations on a gene found on chromosome 4 and link variations at those two locales to the recombination rate. "What's interesting about the SNPs is that the variants have opposite effects on the sexes," says deCODE's chief executive officer Kari Stefansson. According to the new study, one of the locations on the gene, known as RNF212, is associated with high rates of recombination in men, but low rates in women; for the other marker, the gender effect is reversed. "If you were going to design a mechanism to keep rates within [certain] limits you would do exactly this," Stefansson explains about the gender paradigm. "For one generation, it leads to higher recombination rate; for the next generation, it would lead to a lower recombination rate." Overall, the two positions can account for 22 percent of the variability in a man's recombination rate and 6.5 percent of the variability in a female's, the study says.

Chicago's Coop lauded the deCODE efforts, noting that this was the first mapping of a gene that influences recombination in mammals. "I would imagine that the variation that we see in individuals is in part caused by these SNPs," he says. "I think this represents a big step forward in determining the events of human recombination." (From Scientific American Online, February 5, 2008)

Text B. Ethnic Differences Traced to Variable Gene Expression

Finding could explain why ethnic groups suffer from particular common diseases

By Nikhil Swaminathan

Tay-Sachs disease seems to favor Jews of Eastern European descent. Cystic fibrosis has an affinity for Caucasians. Type 2 diabetes strikes Latin Americans and people of African descent more often than it does those of other ethnic groups, appearing at rates of incidence that are 90 and 60 percent higher, respectively, than in Caucasians. Researchers have been conducting studies such as the International HapMap Project--a global effort to catalogue common single-nucleotide variations, such as the addition, deletion or substitution of a base in the code of a gene--to get to the bottom of long-observed correlations between ethnicity and common complex diseases.

But those efforts have borne little fruit, according to Vivian Cheung, a human geneticist at the University of Pennsylvania School of Medicine. So, rather than characterize these individual nucleotide changes in genes, Cheung and geneticist Richard Spielman employed microarray technology--essentially a genome chip that allows a researcher to analyze the expression of many genes at once--to study across Chinese, Japanese and European populations many different traits that are coded for in a type of white blood cell.

Their results, reported in this week's Nature Genetics, were that different ethnic groups not only carried different genes, but there were greater disparities than previously believed in the degrees to which genes that were the same among ethnic groups were expressed. Further, the genes themselves did not control the levels of their own expression, rather noncoding regions adjacent to them determined whether to ratchet up or down the proteins or other functional end products the genes encoded.

The authors of the new study note that large-scale changes to DNA--such as specific substitutions or deletions of genetic material--almost certainly also contribute to differences between ethnic groups. But Cheung says that expression levels likely can explain some of the ethnic underpinnings of Tay-Sachs and cystic fibrosis as well as hypertension, which plagues those of Afro-Caribbean descent at a higher rate than other populations.

From its microarray, the team measured 4,197 genes expressed by cells. (After measuring expression levels of those genes, Cheung, Spielman and their colleagues decided to lump the Japanese and Chinese groups together due to similar results.) When the researchers then compared the Asian populations with the Caucasian sampling, they noted that 1,097, more than 25 percent, of the genes had differing expression levels.

After analyzing some of the nearly 1,100 genes in detail, Cheung and Spielman believe that the expression level discrepancies were due to nucleotide differences in noncoding regions around the genes, and not the genes themselves. "We were able to pinpoint 11 genes where people have different forms of the regulator," Cheung reveals, providing an example: "Let's say that among the Caucasian population, maybe the regulator that turns on the gene more happens to be more frequent--overall the expression level of that gene will be higher. Whereas in the Asian population, more people have the regulator that causes the expression level to be lower."

Steve McCarroll, a population and medical geneticist at the Massachusetts Institute of Technology's Broad Institute says that with so many genetic variants out there, researchers need all the help they can get determining which ones actually will affect cell function. "One of the things that's exciting about this work is that identifying the genetic variants that account for gene expression differences could help the field to find those genetic variants that affect disease risk," he says. (From Scientific American Online, January 9, 2007)

Exercise 4. Who are the following scientists mentioned in the articles? What studies have they carried out?

• Kari Stefansson • George Coop

• Vivian Cheung and Richard Spielman • Steve McCarroll

Exercise 5. Using the information from the texts prove that:

1. DNA recombination is the source of variation in populations.

2. DNA recombination is age and sex related.

3. Ethnic groups suffer from particular common diseases.

4. Not only different genes but difference in expression levels of these genes account for common diseases.

5. Noncoding regions are responsible for the degree of gene expression.

Exercise 6. Put the sentences given below (a-e) into their correct place in the text (1-5).

Ancient Europeans More Diverse, Genetically Speaking, than Modern Ones

Bubonic plague may be responsible for reducing the genetic diversity of present-day Britons

By David Biello

Modern Britons are a cosmopolitan bunch. Peoples from across the globe now make the island home, bringing with them, theoretically, a diverse array of genes. (1) _____ Molecular ecologist Rus Hoelzel of Durham University in England and his European colleagues compared the genetic make up of six English ancestors from the Roman period, 25 from early in the Saxon conquest and 17 from the late Saxon period with the mitochondrial DNA sequences of more than 6,000 modern Europeans and Middle Easterners. "We found higher mitochondrial DNA diversity in ancient England (Roman to Saxon times) than in either modern England or in a combination of northern European countries," Hoelzel says. (2) _______

Even when present-day Europeans were broken down into 10 smaller samples of 48 individuals each, they still were less diverse than their ancestors. (3) ______ ; 6.3 percent of ancients carried it compared with nearly 22 percent of modern Britons and an average of nearly 19 percent of all Europeans.

The CRS haplotype imparts no known special traits in the humans who bear it, but the "black death" may have played a role in increasing its abundance in the modern population. (4) _____ The dread disease could either have increased the proportion of certain haplotypes somehow associated with increased survival or simply led to the extinction of rare haplotypes in families or villages who had a particular susceptibility, Hoelzel says.

Only three small groups—modern peoples from Belarus, Palestine and Turkey—showed similar levels of diversity to these early ancestors, though studies by others have shown that southern Europeans, such as Italians, seem to retain a broader pool of genetic material. (5) ______ , according to researchers, the ancients possessed a more robust array of differing genetic stocks. (From Scientific American Online, August 1, 2007)

1. The 48 ancients bore 36 different haplotypes—a set of variations in the genetic code. But their descendants more commonly carried one particular haplotype, known as Cambridge reference sequence (CRS)

2. It is unclear exactly why contemporary Europeans are less genetically diverse despite a continuing influx of new populations but,

3. This bubonic plague swept Britain (and all of Europe) in the 14th century, killing as much as half of the population, before recurring again in London in the 17th century.

4. “Modern human populations are highly diverse, just less so in northern Europe, at least, than the ancient populations in England."

5. But comparing the genetic material of more than 1,000 contemporary Englishmen with that of 48 of their ancient peers reveals that the ancients had even more diverse genetic codes.

Exercise 7. In the following text the lines are mixed up. Put them in the correct order.

Genetic Study Reveals Similarities between Diverse Populations

By Sarah Graham

genetically very similar, researchers say. A report published today in the journal Science suggests that 93 to 95

from differences in a very small proportion of genetic traits."

people from several continents, suggesting that only a tiny fraction of genetic traits are distinctive to specific

percent of human genetic variation exists among individuals within populations, while differences among major

Marcus W. Feldman of Stanford University and his colleagues analyzed samples from 1,056 people belonging to

alone can provide enough information to group people by population.

52 populations. Specifically, they looked at 377 so-called microsatellites, short segments of DNA that occur in

Though they may speak different languages and eat distinct foods, people from far-flung geographical locations

are populations. This means that visible differences between human groups--such as skin color and skull shape—

result

groups make up less than 5 percent of the variation. But the findings also reveal that even these tiny differences

specific patterns. "Each microsatellite had between four and 32 distinct types," Feldman says. "Most were found in

(From Scientific American Online, December 20, 2002)

Exercise 8. Summarize everything you know about population diversity and genetic mechanisms involved into one report.