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Newsletter #17

The cavemen and their relatives: still in the same village after 3,000 years

By Roger Boyes
The Times

The good news for two villagers in the Sose valley of Germany yesterday was that they have discovered their
great-great- great-great-great-great-great-great-great-great-great- great-great-great-great-great-great-great-great-great- great-great-great-great-great-great-great-great-great-
great-great-great grandparents - give or take a generation or two.

The bad news is that their long-lost ancestors may have grilled and eaten other members of their clan.

Every family has its skeletons in the cave, though, so Manfred Huchthausen,58, a teacher, and 48-year-old surveyor Uwe Lange remained in celebratory mood.

Thanks to DNA testing of remarkably well-preserved Bronze Age bones, they can claim to have the longest proven family tree in the world. "I can trace my family back by name to 1550," Mr Lange said. "Now I can go back 120

Mr Lange comes from the village of Nienstedt, in Lower Saxony, in the foothills of the Harz mountain range. "We used to play in these caves as kids. If I'd known that there were 3,000-year-old relatives buried there I wouldn't have set foot in the place."

The cave, the Lichtensteinhohle, is made up of five interlocked natural chambers. It stayed hidden from view until 1980 and was not researched properly until 1993. The archaeologist Stefan Flindt found 40 skeletons along with what
appeared to be cult objects. It was a mystery: Bronze Age man was usually buried in a field. Different theories were considered. Perhaps some of the bodies had been offered as human sacrifice, or one generation had been eaten by

Scientists at the University of Gottingen found that the bones had been protected by a thick layer of calcium: water dripping through the roof of the limestone cave had helped to create a sheath around the skeletons.

The analysis showed that all the bones were from the same family and the scientists speculated that it was a living area and a ceremonial burial place.

About 300 locals agreed to giving saliva swabs. Two of the cave family had a very rare genetic pattern - and a match was found.

The skulls have been reconstructed using three-dimensional computer techniques and placed in a museum. "It was really strange to look the man deep in the eyes," Mr Lange said.

Over-the-Counter Availability at Local Drug Stores Empowers Those Troubled by a Paternity Question to Get a Definitive Answer through a Fast, Private Process

Press Release
July 28, 2008

November's Test Market Launch Made the Identigene DNA Paternity Test Kit the First DNA Test Ever Sold at Major Retail Outlets

Identigene, an industry pioneer in DNA identification testing, today announced 50,000 Identigene DNA Paternity Test Kits have been purchased since retail sales of the product began in a West Coast test market in November 2007. The kit is the first DNA test ever sold in major retail stores, providing answers to paternity questions quickly with probabilities of paternity greater than 99.99 percent. The self-administered, non-invasive Identigene DNA Paternity Test Kit is now available over-the-counter in 10,000 retail outlets in 45 states just nine months after its retail launch.

"The Identigene DNA Paternity Test Kit was a godsend for my son and me," said Jane Gillespie of St. Clair Shores, Mich. "What are the chances a DNA paternity test kit would become available at a nearby drug store just when my son needed one?" The ex-girlfriend of Gillespie's 17-year-old son had just given birth to a baby girl she claimed was his, but Gillespie had her doubts.

Adoptive parents were ready to pick up the infant at the hospital and wanted Gillespie's son to sign-off as the father, she said. "My son was devastated that he could be the father of a child he wouldn't see again." The timing was awful. "He was planning out his senior year in high school and had finally decided on a career path after graduation. He wanted to do the right thing, but he didn't want his baby to be raised apart from her natural father, as he had.

"I heard about retail sales of Identigene's DNA Paternity Test Kit on the radio earlier that day. And I had only an hour-and-a-half to find a test kit and return to the hospital to obtain a DNA sample from the baby," she said.

The Identigene DNA Paternity Test uses DNA samples of saliva or cheek cells. To use a test kit, the baby, the alleged father and, optionally, the mother have a small amount of DNA collected by swab. The samples, consent forms and a lab fee are sent in a postage-paid envelope to Identigene for processing. Results are available within three to five business days of receipt at the laboratory.

Just days later, Gillespie received lab results: The baby was not her son's. "We were both very relieved. My son felt like a huge burden had been lifted, and I have peace-of-mind knowing I don't have a granddaughter I'll never see.

"Identigene gave my son his life back," said Gillespie. "Now he is beginning his senior year in high school and has been sworn into the delayed entry program of the U.S. Marines, which has been his career dream."

Suggested retail price for an Identigene DNA Paternity Test Collection Kit is $29.99. The laboratory processing fee for the personal peace-of-mind test is $119. An option is available for retail customers who want to use test results in legal proceedings that provides specific collection and secure chain-of-custody procedures for the DNA samples. The processing fee for test results for use in legal proceedings is $319, which includes the lab fee.

Time to Most Recent Ancestor
(And Most Deep History)

Having always been suspicious of the low rate of mutation in Y-STRs used to establish male lineages, blogger Pontikos Dienekes has posted a major critical review of the subject titled "How Y-STR variance accumulates: a comment on Zhivotovsky, Underhill and Feldman (2006)." His critique suggests, among other things, that the age of male haplotypes has been overestimated by 90%, and that the speculative rate of mutation favored by most population geneticists is 3-4 times the observed rate in germline studies of fathers and sons. Furthermore, most estimates neglect rapid expansions of the population and the short-term success of certain male castes.

Read article on Dienekes Anthropology Blog.

Romanov Remains Verified

By Courtney Weaver

New York Times, 07/17/2008, p12

After extensive DNA testing, Russian officials gave final confirmation that remains found last summer in Yekaterinburg belonged to two children of Czar Nicholas II, his only son, Aleksei, and his daughter Maria. The remains were located about 70 yards from where the rest of the family's remains were exhumed in 1991. Laboratories in Russia, the United States and Austria conducted the testing.

Doggy DNA Has Arrived

Thousands of people are happy to pay, about $60 to $170 depending on the method and company chosen, to end the what-do-you-suppose-he-is speculation of mixed-breed dog owners everywhere.DNA testing can disclose what breeds dominate their family trees. The first test was unveiled less than a year ago. Now, consumer interest is growing so fast that more companies are jumping into the doggie-identification business, websites are being enhanced, and additional breeds are being added to testing databases.

Genetic origin, admixture, and asymmetry in maternal and paternal human lineages in Cuba

Mendizabal I, Sandoval K, Berniell-Lee G, Calafell F, Salas A, Martinez-Fuentes A, Comas D.

BMC Evol Biol. 2008 Jul 21;8(1):213

BACKGROUND: Before the arrival of Europeans to Cuba, the island was inhabited by two Native American groups, the Tainos and the Ciboneys. Most of the present archaeological, linguistic and ancient DNA evidence indicates a South American origin for these populations. In colonial times, Cuban Native American people were replaced by European settlers and slaves from Africa. It is still unknown however, to what extent their genetic pool intermingled with and was 'diluted' by the arrival of newcomers. In order to investigate the demographic processes that gave rise to the current Cuban population, we analyzed the hypervariable region I (HVS-I) and five single nucleotide polymorphisms (SNPs) in the mitochondrial DNA (mtDNA) coding region in 245 individuals, and 40 Y-chromosome SNPs in 132 male individuals. RESULTS: The Native American contribution to present-day Cubans accounted for 33% of the maternal lineages, whereas Africa and Eurasia contributed 45% and 22% of the lineages, respectively. This Native American substrate in Cuba cannot be traced back to a single origin within the American continent, as previously suggested by ancient DNA analyses. Strikingly, no Native American lineages were found for the Y-chromosome, for which the Eurasian and African contributions were around 80% and 20%, respectively.

CONCLUSIONS: While the ancestral Native American substrate is still appreciable in the maternal lineages, the extensive process of population admixture in Cuba has left no trace of the paternal Native American lineages, mirroring the strong sexual bias in the admixture processes taking place during colonial times.

Google Wants to Index Your DNA, Too

By Marjorie Backman

Business Week Online, 4/21/2008, p7

Google is investing in genetic screening companies, for instance, Navigenics, which is also backed by start-up venture capital firm Kleiner, Perkins, Caufield & Byers. Navigenics conducts genetic test to determine a person's vulnerability to 18 diseases. Google has invested $4.4 million in 23andMe.

Home DNA test kits cause controversy

By P. Shetty

Lancet 5/24/2008, Vol. 371 Issue 9626, p1739-1740

This article discusses the development of home DNA test kits that purportedly measure disease risks, and concern among doctors about their use outside of medical settings. Two companies providing these tests, deCODEme and 23andME, are discussed. It notes a report by the Human Genetics Council of Great Britain that this type of testing ought to be regulated. The medical ethics problems presented by the tests, including the revelation of health risks without counseling, are discussed. The article quotes Theresa Marteau, a health psychologist from Kings College London, Great Britain, who discusses the need to study the impact of home genetic testing on the lives of people tested.

Prison Facilities Expanding
To Accomodate DNA Storage for Inmates

A rapid expansion of DNA sampling is corresponding with a building and hiring boom in North Dakota and other states to accommodate the collection of hundreds of thousands of new genetic profiles.

Five states are slated to begin new sampling of suspects arrested for felony offenses between July and January 2009. Of those, North Dakota, California, Maryland and Kansas are spending millions of dollars to prepare for the additional testing. South Dakota, which will begin additional sampling in July, built a new lab in 2006.

Meanwhile celebrities are taking up the cause of exonerating wrongfully imprisoned inmates. Natalie Maines, performer in the Dixie Chicks, is fighting for the freedom of three West Memphis, Arkansas men who were convicted of murdering three 8-year-old boys in 1993.

Molecular clock debate: Time dependency of molecular rate estimates for mtDNA: this is not the time for wishful thinking

N Howell et al.

Ed. note Bandelt previously criticized estimates of mutation rates. Here is an important reply with sweeping consequences for restoring the role of selection in evolutionary theory.

We must respond to the recent Commentary by our colleague Dr Bandelt (Bandelt, 2008). In brief, he is highly critical of the concept that rate estimates of mtDNA sequence evolution are time dependent and fit an exponential decay model (Ho et al., 2007). This is a complex issue, but we argue that many of Dr Bandelt's arrows miss the target.

Dr Bandelt believes that human mtDNA sequences have evolved according to some simple clock-like process that allows highly accurate and reliable time estimates for coalescent events during human evolution (a molecular 'stopwatch'). In his Commentary, he calls for greater precision of the mtDNA clock than is feasible, such that one can accurately differentiate events that occurred 15 ky ago from those that occurred 20 ky ago. This wishful thinking ignores two realities. Firstly, there is a steady accumulation of reports that human mtDNA does not evolve in a clock-like manner (Howell et al., 2007 and references therein). Sequence sets that 'pass' a robust clock test are the exception. Secondly, we lack adequate calibration points for accurate time estimates, even if there were a human mtDNA clock (Pulquério and Nichols, 2007).

The criticism is made that Ho et al. (2007), analyzed human mtDNA hypervariable region I sequences, and—according to the current view of Dr Bandelt—this segment of the control region does not contain sufficient phylogenetic signal for robust analysis. However, time dependent rate variation is also seen in analyses of the mtDNA coding region (Ho et al., 2007; see also further comments below).

Dr Bandelt again takes the opportunity to dismiss the discrepancy between mtDNA rate estimates from pedigree analyses and those from phylogenetic analyses. We disagree that the pedigree rate is not well defined. It has an explicit operational definition and is, in fact, more empirical and less model-dependent than phylogenetic rate estimates (Howell et al., 2003). Dr Bandelt also makes the unsubstantiated charge that pedigree analyses '...seem to suffer from ascertainment bias and...sequence errors...'. We cannot find evidence for either and the issues he raises have been addressed previously (Howell et al., 2003). On the other hand, it is Dr Bandelt who has concluded that many mtDNA sequence sets, often used for phylogenetic analyses, contain a high proportion of errors.

Despite his criticisms, Dr Bandelt eventually admits that there is a discrepancy in the rate estimates, but that it is not an order of magnitude. Our meta-analysis confirmed that the pedigree rate was less than one set of phylogenetic rates by an order of magnitude (Howell et al., 2003). A more significant problem is that phylogenetic rate estimates vary widely, something that should trouble 'stopwatchers'. It is worth noting at this point that a three- to fourfold pedigree/phylogenetic discrepancy has been observed for rate estimates of the Y chromosome microsatellite sequences (Zhivotovsky et al., 2006 and references therein). Our disagreements with Dr Bandelt on these technical issues are important, but they should not detract from the point of general significance: the pedigree rate of substitution is significantly less than the molecular rate of mtDNA mutation but greater than the 'zone' of phylogenetic rate estimates. Why would there be any difference between rate estimates, if there is a simple mtDNA molecular clock?

Selection has been a major force acting on mtDNA evolution and this finding has profound implications for the operation of an mtDNA clock. Some investigators have suggested a role for positive selection, but it is not discussed further, because such a role has failed to obtain support. Instead, here, we focus on purifying (negative) selection and its consequences for the rate of sequence evolution. While purifying selection operates at the level of the germline (Stewart et al., 2008), it does not act instantaneously, and, instead, a substantial proportion of slightly deleterious mutations are lost continuously from the mtDNA gene pool over a prolonged period of time (Elson et al., 2004; Kivisild et al., 2006; Howell et al., 2007; Elson et al., submitted for publication). As a result of this selection acting throughout the human mtDNA phylogenetic tree, relatively more mutations have been lost in older branches (for example, mtDNAs from Africans) than in younger branches (for example, mtDNAs from Europeans). Dr Bandelt also refers to these results in his Commentary, but he does not 'connect the dots' and point out that the continuous loss of mtDNA mutations on a similar timescale as human evolution will necessarily result in time-dependent rates of substitution.

It must be emphasized, finally, that the case for a 'slow' process of purifying selection, one that leads to time-dependent rates, does not rely on measurements of substitution rates in pedigrees. The latest example is the impressive study of fish mtDNA evolution (Burridge et al., 2008) where time-dependent rates are observed and , at least in part, due to the operation of purifying selection. However, pedigree rates do offer us an important insight to the early phase of selection (and other important evolutionary processes such as random genetic drift and bottlenecks) and this is why we must note here our disagreements with Dr Bandelt.

Our comments must also include the caution that there is much that we do not understand about the sequence evolution of human mtDNA. (a) The decay curve of mtDNA substitution rates needs greater precision (see especially Burridge et al., 2008). (b) Purifying selection appears to play a major role but the issue of positive selection remains unresolved. (c) Random genetic drift is also a prominent feature of human mitochondrial genetics, largely due to the germline bottleneck (Cree et al., 2008). There is a conundrum, because, according to standard population genetic models, drift tends to minimize or diminish the effects of purifying selection. (d) It is remarkable that the mtDNA control and coding regions do not appear to have evolved in lockstep (Howell et al., 2007), and the reasons for this 'decoupling' warrant investigation.

For more than a decade, Dr Bandelt has been wholehearted in his efforts to simplify mtDNA evolution and, especially, to champion the use of simple mtDNA clocks. It is our contrary view, based both on our research and that of many other groups, that mtDNA evolution is not clock-like and that the evidence for time-dependent rates should not be dismissed. When it comes to mtDNA, one should not use a sundial as a stopwatch.
Top of page

1. Bandelt H-J (2008). Time dependency of molecular rate estimates: tempest in a teacup. Heredity 100: 1–2. | Article | PubMed |
2. Burridge CP, Craw D, Fletcher D, Waters JM (2008). Geological dates and molecular rates: fish DNA sheds light on time dependency. Mol Biol Evol 25: 624–633. | Article | PubMed | ChemPort |
3. Cree LM, Samuels DC, De Sousa Lopes SC, Rajasimha HK, Wonnapinij P, Mann JR et al. (2008). A reduction of mitochondrial DNA molecules during embryogenesis explains the rapid segregation of genotypes. Nat Genet 40: 249–254. | Article | PubMed | ChemPort |
4. Elson JL, Turnbull DM, Howell N (2004). Comparative genomics and the evolution of human mitochondrial DNA: assessing the effects of selection. Am J Hum Genet 74: 229–238. | Article | PubMed | ISI | ChemPort |
5. Ho SYW, Shapiro B, Phillips M, Cooper A, Drummond AJ (2007). Evidence for time dependency of molecular rate estimates. Syst Biol 56: 515–522. | Article | PubMed | ISI |
6. Howell N, Elson JL, Howell C, Turnbull DM (2007). Relative rates of evolution in the coding and control regions of African mtDNAs. Mol Biol Evol 24: 2213–2221. | Article | PubMed | ChemPort |
7. Howell N, Smejkal CB, Mackey DA, Chinnery PF, Turnbull DM, Herrnstadt C (2003). The pedigree rate of sequence divergence in the human mitochondrial genome. There is a difference between phylogenetic and pedigree rates. Am J Hum Genet 72: 659–670. | Article | PubMed | ISI | ChemPort |
8. Kivisild T, Shen P, Wall DP, Do B, Sung R, Davis K et al. (2006). The role of selection in the evolution of human mitochondrial genomes. Genetics 172: 373–387. | Article | PubMed | ISI | ChemPort |
9. Pulquério MJF, Nichols RA (2007). Dates from the molecular clock: how wrong can we be? Trends Ecol Evol 22: 180–184. | Article | PubMed |
10. Stewart JB, Freyer C, Elson JE, Wredenberg A, Cansu Z, Trifunovic A et al. (2008). Strong purifying selection in transmission of mammalian mitochondrial DNA. PLoS Biol 6: e10. | Article | PubMed | ChemPort |
11. Zhivotovsky LA, Underhill PA, Feldman MW (2006). Difference between evolutionarily effective and germ line mutation rate due to stochastically varying haplogroup size. Mol Biol Evol 23: 2268–2270. | Article | PubMed | ChemPort |
Editor's suggested reading
1. Anisimova M, Liberles DA (2007). The quest for natural selection in the age of comparative genomics. Heredity 99: 567–579. | Article |
2. Berlin S, Tomaras D, Charlesworth B (2007). Low mitochondrial variability in birds may indicate Hill–Robertson effects on the W chromosome. Heredity 99: 389–396. | Article | PubMed | ChemPort |

Paternity Tests Available in Drugstores
By Catherine Arnst

Business Week, 4/14/2008 Issue 4079, p15-15t

The drugstore Rite Aid began selling paternity kits in the U.S. on March 25, 2008. The kits, which are made by company Identigene, allow users to take DNA samples from children and parents, which are then sent to a facility for analysis. The article reports that the tests cannot be used in court, but that they are at least 99 percent accurate.

Relative Rates of Evolution in the Coding and Control Regions of African mtDNAs

By Neil Howell et al.

Molecular Biology and Evolution 2007 24(10):2213-2221

Molecular Clock Does Not Tick at Uniform Rate Across the Genome

Implications for Evolution: Quantum Leaps and Purifying Actions

Reduced median networks of African haplogroup L mitochondrial DNA (mtDNA) sequences were analyzed to determine the pattern of substitutions in both the noncoding control and coding regions. In particular, we attempted to determine the causes of the previously reported (Howell et al. 2004) violation of the molecular clock during the evolution of these sequences. In the coding region, there was a significantly higher rate of substitution at synonymous sites than at nonsynonymous sites as well as in the tRNA and rRNA genes. This is further evidence for the operation of purifying selection during human mtDNA evolution. For most sites in the control region, the relative rate of substitution was similar to the rate of neutral evolution (assumed to be most closely approximated by the substitution rate at 4-fold degenerate sites). However, there are a number of mutational hot spots in the control region, ~3% of the total sites, that have a rate of substitution greater than the neutral rate, at some sites by more than an order of magnitude. It is possible either that these sites are evolving under conditions of positive selection or that the substitution rate at some sites in the control region is strongly dependent upon sequence context. Finally, we obtained preliminary evidence for "nonideal" evolution in the control region, including haplogroup-specific substitution patterns and a decoupling between relative rates of substitution in the control and coding regions.

Genetic-screening companies face legal battle

Nature 453, 1148-1149 (2008)

The state of California is clamping down on companies that offer direct-to-consumer genetic testing in a move that threatens the burgeoning industry. Meredith Wadman looks at a grey area in US regulation.

Ed. Note: Genetic screening is a quasi-medical form of DNA testing, not at all the same as ancestry testing.

By Meredith Wadman

Last Wednesday, as California governor Arnold Schwarzenegger prepared to tell a biotechnology industry convention in San Diego that his state “is one of the best places to set up shop”, Kári Stefansson was opening a letter that had just landed on his desk at deCODE genetics in Reykjavik, Iceland.

The letter read: “It has come to the attention of the California Department of Public Health…that deCODEme Genetics is in violation of California law” for failing to have a clinical laboratory licence in the state and offering genetic tests to consumers resident in the state without a physician's order. It gave deCODE until 23 June to submit a plan showing how it would correct the situation, or face “civil and/or criminal sanctions”.

Stefansson's high-profile company is one of 13 genetic-testing firms that have been targeted during the past two weeks by the California agency with a letter to “cease and desist” selling tests to California's residents. The directive poses a serious challenge to plans for a new era of Internet-based, direct-to-consumer genetic testing. The companies include Californian businesses 23andMe and Navigenics, which have begun marketing test packages based on genome-wide arrays within the past six months, and DNATraits.com, based in Houston, Texas, which counsels prospective parents on the genetic risks faced by their future offspring.

DNA Direct, a San Francisco-based firm founded in 2003 that offers tests for familiar mutations in well-characterized genes such as BRCA1 and BRCA2 , which convey an increased risk of breast cancer, did not receive a letter.

“If these companies were constrained from reaching out to consumers directly, it would certainly cause some near-term difficulty for their business,” says life-sciences analyst John Sullivan at Leerink Swann, an investment bank based in Boston.

During a public meeting on 13 June, Karen Nickel, California's chief of laboratory field services, who wrote the letter, said that consumer complaints had triggered an investigation into 25 companies, of which 13 were ultimately sent letters. Nickel told the meeting: “We [are] no longer tolerating direct-to-consumer genetic testing in California.” Under California law, the companies could be fined up to US$3,000 per day for each violation if there is no “immediate jeopardy” to state residents — and from $3,050 to $10,000 per day if there is.

23andMe declined an interview request. It released a statement emphasizing that it is an “informational service”, and said it is “eager to work with” regulators in California and elsewhere to develop appropriate regulations to govern the nascent industry.

But two of the companies dispute the charges in the letter. Mari Baker, chief executive of Navigenics, based in Redwood Shores, says that its tests are read by a licensed, certified laboratory and that a company physician is involved both in the approval of a genetic-test order and when the results are released to a customer. “It's important to do this the right way,” says Baker. “And that we are doing. So this has come as quite a surprise. The only conclusion we can come to is we have not properly informed the state as to all the steps we have in place. We have reached out to them to try to schedule such a meeting.”

Stefansson says that deCODE is not marketing to California residents; its website lists California among several states for which the company's deCODEme Genetic Scan “may omit certain information” because of state law. He says that his company is in the process of trying to obtain a California licence, but that the state has been unresponsive. He is a physician and oversees the ordering process for deCODE, he says, adding that a large proportion of the test requests the company receives are from people's personal physicians.

“It doesn't increase your risk. It measures your risk.”

Even so, he calls the legality of California's requirement that a physician order a genetic test “questionable”. He says: “I don't think that they can basically tell the people of California that 'you cannot order a test like this for yourself without going to a physician'. I don't think they can raise that kind of barrier.” He argues that a genetic test is not a medical intervention like, say, a prescription for a cholesterol-lowering drug. “It doesn't increase your risk. It doesn't decrease your risk. It measures your risk. It's a description of who you are.”

The state Department of Public Health —which is no longer making Nickel available for interviews — declined to say whether a company-employed physician who oversees orders initiated by customers through the Internet would meet its requirement that a physician order the genetic test.

That has been a grey area among regulators and policy-makers, says Kathy Hudson, director of the Genetics and Public Policy Center at Johns Hopkins University in Washington DC. “Is a doctor who is your personal physician, who has a fiduciary responsibility to you, the same as a company doctor? Is it really the same thing to call up a company who is trying to sell you a product and have their doctor, who receives a pay-cheque from them, advise you? To me, it is not the same thing.”

The Californian law does not prevent state-based companies from marketing the tests to consumers residing outside the state. But a muddle of different state laws across the United States provides a confusing array of regulations on the issue.

New York's Department of Public Health has sent similar letters to 26 companies since last November. In response, 23andme and Navigenics have submitted business plans that the department is reviewing, says its spokesman Jeffrey Hammond. “The good news for both 23andme and Navigenics is the labs they are proposing they use for their lab work are known to the department and have a history of compliance with us.” Hammond adds: “Our goal is not to levy fines. It is to bring companies who want to do business in New York into compliance with state law.”

Hudson says that the California and New York letters point out the conspicuous lack of unifying federal regulation of genetic testing. The law “is very inconsistent from state to state at a time when the risks to consumers do not vary state to state — and when we have businesses that are certainly operating state to state”.

Ryan Phelan, chief executive of DNA Direct, says that the one-size-fits-all approach of the letters is a cause for concern, because tests being offered range from those predicting serious diseases to “fun to know” information with no bearing on a person's health. “There is going to be increasingly a need for nuanced regulation. All genetic tests should not be considered the same.”

Genome-wide association studies all the rage

This month's Nature Reviews Genetics (vol. 9, July 2008) and an upcoming conference sponsored by The Wellcome Trust on the genomics of common diseases highlight a growing trend in genetics -- genome-wide association studies (GWAS). Thanks to improvements in high-throughput sequencing, medical researchers can now scan and scout through the entire genome looking for clues to the inheritance of disease.

According to the NIH, a genome-wide association study is defined as any study of genetic variation across the entire human genome that is designed to identify genetic associations with observable traits (such as blood pressure or weight), or the presence or absence of a disease or condition. Whole genome information, when combined with clinical and other phenotype data, offers the potential for increased understanding of basic biological processes affecting human health, improvement in the prediction of disease and patient care, and ultimately the realization of the promise of personalized medicine.

In addition, rapid advances in understanding the patterns of human genetic variation and maturing high-throughput, cost-effective methods for genotyping are providing powerful research tools for identifying genetic variants that contribute to health and disease.

In concert with the growth of GWAS's, a new national database has been founded. dbGaP (Database of Genotypes and Phenotypes) was developed by the National Center for Biotechnology Information (a division of the National Library of Medicine of the NIH) to archive and distribute the results of studies that have investigated the interaction of genotype and phenotype. dbGaP will serve as the NIH GWAS data repository.

Psychiatric genetics: progress amid controversy

Margit Burmeister et al.

Nature Reviews Genetics 9, 527-540 (July 2008)

* Most psychiatric disorders are highly heritable, yet few reproducible genetic risk factors have been identified by linkage analysis and candidate gene or genome-wide association studies.
* Large genomic rearrangements have been found in a subset of patients with autism and schizophrenia, suggesting that recurrent and/or new mutations are involved in psychiatric disorders.
* Several confirmed genetic risk factors of relevance to psychiatric disorders are with endophenotypes — that is, with quantitative phenotypes related to psychiatric disorders — rather than with diagnoses themselves.

* The incorporation of environmental risk factors into analysis has helped to elucidate and identify some genetic risk factors. Longitudinal studies will be needed to identify gene-by-environment effects.
* Psychiatric symptoms have a role in some Mendelian disorders that have known causes.
* Unique families with rare syndromes have led to the identification of some common genetic risk variants.
* The genetics of psychiatric disorders is complex and needs to be approached from several angles. It is therefore insufficient to focus only on linkage and association studies of clinical categories.
* Increased sample size and meta-analyses of large existing studies might allow the identification of common risk variants of psychiatric disorders.
* Future work will need to incorporate additional factors: alternative phenotypes; recurrent new mutations and rare, 'private' mutations that are not detectable by genome-wide association; the interaction of environment with genetic risk factors; and, by bioinformatic means, our growing knowledge of expression differences and biological pathways.

Genomics, like Medicine, Slow
When It Comes to Women

Read All About It--The First Female Genome! Or Is It?

Martin Enserink

Science 6 June 2008:
Vol. 320. no. 5881, p. 1274

Last week's announcement that scientists had finally sequenced the genome of a woman was hailed as a victory for equality. But it raised eyebrows as well, because the data have not been put in the public domain nor analyzed, let alone published.

This time it's personal

Nature 453, 697 (5 June 2008)


The next head of the US National Human Genome Research Institute will need to be equipped to deal with the scientific, political and societal challenges presented by the burgeoning era of personal genomics.

On 28 May, Francis Collins announced that he is stepping down after 15 years as head of the US National Human Genome Research Institute (NHGRI), where he helped lead the international effort to sequence the entire human genetic code (see page 710). His departure is an opportunity to take stock of his legacy and to contemplate the future of the institute he leaves at a crossroads in its existence.

Collins took up his post in 1993, four years before the NHGRI became a separate branch of the National Institutes of Health (NIH) in Bethesda, Maryland. He proved to have a rare combination of political acumen, scientific talent and administrative skill — abilities that allowed him to steer the institute through numerous challenges and reinventions while remaining about as well-liked as it's possible for an institute director to be.

In the 1990s, for example, successful completion of the public arm of the Human Genome Project was in doubt until Collins rallied its members to respond to a challenge led by Craig Venter, a former NIH scientist who was mounting a sequencing effort for commercial purposes. After the genome project was successfully concluded in 2003, some in Washington began asking whether the NHGRI was still needed. Collins made the case — rightly — that the post-genomic era would be even more exciting and challenging than the race to sequence the genome. He and the NHGRI helped prove that by launching a variety of follow-on efforts, including the International HapMap Project, ENCODE (the Encyclopedia of DNA Elements) and, most recently, the 1,000 Genomes Project — an attempt to create an atlas of human genetic variation in unprecedented detail.

The National Human Genome Research Institute may become more of a target for politicians who feel it has run its course.

Those initiatives have been possible because of technological improvements that dramatically cut the cost of sequencing — improvements for which Collins deserves considerable credit, as he made them funding priorities. The lower costs have accelerated efforts worldwide to clarify the genetic basis of evolution by filling out the 'tree of life'; more than 100 non-human species have been or are now being sequenced.

Collins also deserves credit for making the ethical, legal and social issues of genomics a high priority at the NHGRI. He says he is particularly satisfied with recent passage through Congress of the Genetic Information Nondiscrimination Act, for which he had long been a passionate advocate. Certainly the passage was timely: cheaper sequencing has ushered in a new era of 'personal genomics', in which companies are offering all manner of tests that claim to reveal a person's susceptibility to conditions such as Alzheimer's disease.

Although Collins says he has no concrete plans for after he steps down on 1 August, speculation is rife that he could serve as NIH director or White House science adviser in the next presidential administration. In the meantime, the future of the NHGRI is more cloudy than his own. The funding situation at the NIH has been gloomy for years, with flat budgets stifling many potentially worthy projects. And with Collins gone, the NHGRI may become more of a target for politicians who feel it has run its course.

Ideally, then, Collins's successor will display both his scientific and political skills. He or she will have to continue to pursue ambitious new projects on the scale of 1,000 Genomes. At the same time, the new director will have to ensure that the implications and applications of those projects are fully explained to all concerned, from the medical profession and insurance companies to politicians and the public. Genomics is now at a point where the science and technology are moving much faster than society's ability to assimilate and make sense of the information. Bridging this gap — a task at which Collins worked very hard — will be his successor's major challenge.

Senate Protects Confidentiality
of Personal Genetic Data

Measure would bar use of information by insurers, employers

Baltimore Sun
April 25, 2008

By Jonathan D. Rockoff

WASHINGTON - Coming to grips with the growing role of genetic testing in American life, Congress acted yesterday to outlaw the use of genetic information in employment or insurance decisions.

The Senate approved a measure, which the House of Representatives is expected to ratify and President Bush to sign, that would become the first federal law dealing with the growing role of genetics in the prediction, diagnosis and individualized treatment of disease.

Many patients who could benefit have refused genetic testing out of fear of discrimination, experts say . . . Read article.

Paleo-Eskimo mtDNA Genome Reveals Matrilineal Discontinuity in Greenland

M. Thomas et al.

Published Online May 29, 2008
Science DOI: 10.1126/science.1159750

The Paleo-Eskimo Saqqaq and Independence I cultures, documented from archaeological remains in Northern Canada and Greenland, represent the earliest human expansion into the New World’s northern extremes. However, their origin and genetic relationship to later cultures is unknown. We sequenced a mitochondrial genome from a Paleo-Eskimo human, using 3400- to 4500-year-old frozen hair excavated from an early Greenlandic Saqqaq settlement. The sample is distinct from modern Native Americans and Neo-Eskimos, falling within haplogroup D2a1, a group previously observed among modern Aleuts and Siberian Sireniki Yuit. This suggests that the earliest migrants into the New World’s northern extremes derived from populations in the Bering Sea area, and were neither directly related to Native Americans nor the later Neo-Eskimos that replaced them.

This was the first near-complete ancient mtDNA genome ever published.

Rare Northern Israeli Population
Provides Window into Dim Genetic Past

The Druze: A Population Genetic Refugium of the Near East

Liran I. Shlush et al.

Phylogenetic mitochondrial DNA haplogroups are highly partitioned across global geographic regions. A unique exception is the X haplogroup, which has a widespread global distribution without major regions of distinct localization.

Principal Findings

We have examined mitochondrial DNA sequence variation together with Y-chromosome-based haplogroup structure among the Druze, a religious minority with a unique socio-demographic history residing in the Near East. We observed a striking overall pattern of heterogeneous parental origins, consistent with Druze oral tradition, together with both a high frequency and a high diversity of the mitochondrial DNA (mtDNA) X haplogroup within a confined regional subpopulation. Furthermore demographic modeling indicated low migration rates with nearby populations.


These findings were enabled through the use of a paternal kindred based sampling approach, and suggest that the Galilee Druze represent a population isolate, and that the combination of a high frequency and diversity of the mtDNA X haplogroup signifies a phylogenetic refugium, providing a sample snapshot of the genetic landscape of the Near East prior to the modern age.

Phylogenetic clustering of mtDNA haplogroups has been found to correlate with geography, such that different haplogroups often correspond to specific geographic origins [1]. For example, the L haplogroup is a hallmark of the African continent, where almost 95% of the inhabitants belong to the different lineages of this mtDNA haplogroup. Haplogroup L can also be found at low frequencies in other regions of the world due to migration events. Similarly, haplogroups A and B are predominantly found among Native Americans[1]. Haplogroup X is one of the exceptions to this pattern of limited geographical distribution, and is found at low frequencies among West Eurasians[2], northern groups of Native Americans[3], as well as in northern Africa and the Near East[4]. A very high global genetic diversity has been reported for haplogroup X[4].

Haplogroup X is further divided into two subclades. Subhaplogroup X1 was found to be largely restricted to the Afro-Asiatic-speaking populations of northern Africa and the neighboring areas, suggesting a possible geographic diffusion of X1 along the coast of the Mediterranean and the Red Sea. Subhaplogroup X2 is characterized by a much wider geographic range, but at the same time by very low frequencies in the populations of the regions where it is found[4]. No population or geographic region has been identified to date, in which haplogroup X and its major subhaplogroups are found at both high frequency and high diversity, which could provide a potential clue as to their geographic origin. Here we suggest that the Druze population of northern Israel may represent just such a population.

The Druze population has a unique historical, social and demographic structure, which is closely connected with their religion. The contemporary Druze population constitutes a small minority in four countries of the Near East: Syria, Lebanon, Israel and Jordan. In total, the estimated population number is fewer than 1,000,000 in the Near East and fewer than 100,000 in the Druze Diaspora. The Israeli Druze population is estimated at 150,000, and is distributed over three geographical subregions: the Carmel, the Galilee, and the Golan Heights. It has been postulated according to historical records that the origin of the Druze in each of these regions is different. Although the Druze represent a small percentage of the total population of the countries of the Near East in which they reside, their concentration in mountainous districts has produced a compact social structure, resulting in a nearly exclusive majority in some geographical regions, and therefore a low frequency of admixture with other populations. Druze customs strongly favor marriage within the same village or the same geographical area[5]. This social structure has turned the Druze into transnational isolates – a population which remains genetically isolated largely through the social practice of endogamy and consanguinity, despite being found in the midst of larger population majorities in multiple nationalities or countries[6]. Furthermore, unlike other monotheistic religions, the Druze tenets strictly close their religion to new adherents, thus forbidding admixture with other populations.

Previous studies described a high frequency with a low diversity of both the X1 and X2 subhaplogroups in the Druze population[4], [7]. This was attributed to a founder effect, genetic drift, and population expansion[4]. These explanations contradict Druze oral traditions, which claim that while the religion was revealed at the time of the “Dawa” (1017 A.C.E.), its adherents came from heterogeneous ancestral origins dating back further in antiquity. We sought to resolve this apparent contradiction, and at the same time re-examine the overall mtDNA and Y-chromosome diversity using a sampling strategy which might be more appropriate for the social structure and marriage practices of the Druze population. In so doing, we uncovered an unexpectedly high diversity of Druze X-haplogroup lineages, which together with its high frequency suggest that this population provides a glimpse into the past genetic landscape of the Near East, at a time when the X haplogroup was more prevalent.

What's Next? Doggy DNA, That's What!


People 12/31/2007, Vol. 68, Issue 27

Dog DNA testing is all the rage, so People Magazine asked genetics experts at Metamorphix Inc. to help readers identify the breeds of their mystery mutts. One dog from New Canaan, Connecticut, named Missy, revealed shar-pei, pug, chow chow. "We'd Call It a . . . 'Chug Chow,'" said the company.

Did Humans Marry or Kill Neanderthals
And Other Humanoids They Encountered?

"Genetic evidence and the modern human origins debate"

J H Relethford

Heredity (2008) 100, 555–563, published online 5 March 2008

A continued debate in anthropology concerns the evolutionary origin of 'anatomically modern humans' (Homo sapiens sapiens). Different models have been proposed to examine the related questions of (1) where and when anatomically modern humans first appeared and (2) the genetic and evolutionary relationship between modern humans and earlier human populations. Genetic data have been increasingly used to address these questions. Genetic data on living human populations have been used to reconstruct the evolutionary history of the human species by considering how global patterns of human variation could be produced given different evolutionary scenarios. Of particular interest are gene trees that reconstruct the time and place of the most recent common ancestor of humanity for a given haplotype and the analysis of regional differences in genetic diversity. Ancient DNA has also allowed a direct assessment of genetic variation in European Neandertals. Together with the fossil record, genetic data provide insight into the origin of modern humans. The evidence points to an African origin of modern humans dating back to 200 000 years followed by later expansions of moderns out of Africa across the Old World. What is less clear is what happened when these early modern humans met preexisting 'archaic human' populations outside of Africa. At present, it is difficult to distinguish between a model of total genetic replacement and a model that includes some degree of genetic mixture.

China Divided into North and South
Through Mitochondrial DNA Lineages

A spatial analysis of genetic structure of human populations in China reveals distinct difference between maternal and paternal lineages

Fuzhong Xue et al.

European Journal of Human Genetics (2008) 16, 705–717; published online 23 January 2008


Analyses of archeological, anatomical, linguistic, and genetic data suggested consistently the presence of a significant boundary between the populations of north and south in China. However, the exact location and the strength of this boundary have remained controversial. In this study, we systematically explored the spatial genetic structure and the boundary of north–south division of human populations using mtDNA data in 91 populations and Y-chromosome data in 143 populations. Our results highlight a distinct difference between spatial genetic structures of maternal and paternal lineages. A substantial genetic differentiation between northern and southern populations is the characteristic of maternal structure, with a significant uninterrupted genetic boundary extending approximately along the Huai River and Qin Mountains north to Yangtze River. On the paternal side, however, no obvious genetic differentiation between northern and southern populations is revealed.

New directions in the anthropology of migration and multiculturalism

Steven Vertovec

Ethnic and Racial Studies, Volume 30, Number 6, November 2007, pp. 961-978(18)


It is a kind of boom time for the anthropology of migration. Anthropologists are currently studying a wide range of migration-related topics. Many of them, of course, are not entirely new: anthropologists have been researching migration dynamics and impacts since at least the 1930s (most notably within the Manchester School of anthropology). Since the 1970s the discipline's burgeoning interst in ethnicity has largely entailed research on post-migration communities. Since the 1990s, migrant transnationalism has become one of the most fashionable topics. There is still much to do in research and theory around migration, not least with regard to public debates around multiculturalism. This introduction suggests a number of possible new directions for anthropological inquiry into migration and multiculturalism, and summarizes the special issue's contributing articles in light of their contributions toward moving the discipline in these directions.