The Genetic Genealogist

The CCR5 gene encodes a chemokine receptor (a long name for a protein that sits in the walls of our cells). When the body has been invaded by a pathogen such as a cold virus, CCR5 plays an important role in fighting that virus. Smart viruses such as HIV-1, however, hijack the CCR5 protein and use it to sneak into CD4+ T cells & macrophages.

In some populations the CCR5 gene has experienced a mutation that deleted 32 basepairs in the gene sequence. The mutation prevents the expression of the protein on the cell surface. As a result, people with this mutation show some degree of protection from certain viruses. In fact, homozygosity of the CCR5-D32 allele (meaning BOTH copies of the gene are mutated) leads to “nearly complete resistance to HIV-1 infection.” People with only 1 copy are as much as 70% resistant! Surprisingly, homozygotes do not show any other problems as a result of the mutation.

The CCR5-D32 allele is absent among Amerindians and East Asians but is found in some African populations. The allele is found in high concentration among Eurasians. Indeed, the average frequency of the allele among European populations is 10%. The fact that the allele is found in such a high percentage in one population and not at all in another suggests that there was a strong selective pressure in favor of that allele. The source of that genetic pressure is still being debated by scientists. The early favorite was the Black Death, the Bubonic plague that swept through Europe in the Fourteenth century. The picture above is of Yersinia pestis, the bacterium that causes the plague.

Other researchers have hypothesized that the period of selective pressure created by the Bubonic plague, roughly 400 years, was not long enough for the overwhelming presence of the gene to appear. These researchers suggest that smallpox, which has killed as many people as the plague over a much longer time period, could have provided sufficient selective pressure. To support this conclusion it is proposed that the continued presence of the mutated gene in the face of lowered genetic fitness is due to the fact that smallpox was only eradicated recently while the plague hasn’t been a serious problem in 250 years. Indeed, a cousin of the smallpox virus has been shown to use CCR5 to enter host cells. Thus, CCR5-D32 may provide resistance to smallpox.

So what does this have to do with genetic genealogy? Family Tree DNA offers CCR5 testing through their advanced test options (meaning you have to already have your DNA stored at the company). If a person is tested and has one or two copies of the CCR5-D32 allele, it is very likely that the person has European ancestry.

I would caution that CCR5 testing should NOT be used as a diagnostic test for medical conditions. In my opinion the CCR5 test should be only be used to explore one’s ancestry. The presence of the CCR5-D32 allele implies that a person has European ancestry, NOT that they have a license to engage in risky behavior!

My first foray into genetic genealogy took place in 2003 when I ordered the mtDNAPlus (which sequences both HVR1 and HVR2) from Family Tree DNA.

Like so many other genealogists, I had been unable to trace my maternal line as far as I would have hoped. My most distant ancestor, Sarah L. Bodden, was born in 1846 in the Cayman Islands and had died in 1914 in Honduras. No one knew anything about Sarah’s parents or her life, and given the location and the difficulty of research I felt that this line had little prospect of development. It was a perfect opportunity to employ genetics.

Inside (almost) every one of my 50 trillion cells (that’s 50,000,000,000,000!!!) there is a tiny circle of DNA that has been given to me, most likely unchanged, in a direct line from Sarah through 125 years, 5 generations, and across 1750 miles. By sequencing a small part of the DNA I could identify from which branch of the “maternal family tree” Sarah descended. Based on the information I had managed to put together, I predicted that Sarah was a descendant of English immigrants who settled the Cayman Islands and would thus possess mtDNA belonging to a European lineage.

When the results came back, I was astonished to learn that Sarah’s mtDNA belonged to Haplogroup A, one of the five haplogroups found among Native Americans (the others being B, C, D, and X). This meant that Sarah and her mother, two individuals I knew nothing about, were descendants of Native Americans, most likely from Central America (to date I have not found an exact match to my mtDNA). At some point in history a male in the Bodden family had married a woman with Native American ancestry. I now had a connection with this distant ancestor that I couldn’t have made just a few years ago. Instead of recently crossing the Atlantic Ocean on a boat as I had predicted, my mtDNA had traveled in the opposite direction across the entire globe. Genetic genealogy allowed me to explore the ancient roots of my mtDNA, the time capsule that resides in every one of our cells.

Senator Edward Kennedy (D-Massachusetts) proposed a piece of legislation before the United States Senate on 1 March 2007 called the “Laboratory Test Improvement Act.” The Act is proposed as a series of amendments to the Federal Food, Drug, and Cosmetic Act (FFDCA).

Sen. Kennedy’s statement(pdf) before the Senate, found in the Congressional Record from this month, defines his goal as “[ensuring] the quality of clinical tests used every day in hospitals and doctors’ offices across the country.” Additionally, he pointed out that the “tests are being used to diagnose illnesses, predict who is most susceptible to specific diseases, and identify persons who carry a genetic disease that they could pass on to their children.”

On his website Sen. Kennedy posted a news release that clarified his position:

“The legislation will mandate that all providers of “homebrew” laboratory tests provide the FDA with evidence that verifies their analytical and clinical validity. All of the information submitted to the FDA will be compiled into a database, which will subsequently be made available to the public on the Internet. Presently, an overwhelming majority of the laboratory tests employed by health care facilities are homebrew tests that have not been approved by the FDA. In some instances, homebrew tests are used to diagnose Huntington’s disease and susceptibility to breast cancer. As such, the results of homebrew tests affect the lives of thousands of Americans and their families each and every year.”

Sen. Smith (R-Oregon), co-sponsor of this Act and Ranking Member of the Senate Special Committee on Aging, chaired a hearing in 2006 entitled “At Home DNA Tests: Marketing Scam or Medical Breakthrough?” that addressed the lack of regulation of “homebrew” genetic testing products.

So will this legislation affect the thousands of genetic genealogy tests sold by DNA laboratories in the United States? Most likely not, since genetic genealogy tests do not appear to fall under the ‘intent’ of the Laboratory Test Improvement Act. Rather, it would seem to include companies such as the nutrigenomics company MyCellf (discussed in a previous post) which screens DNA for gene variants associated with disease. Currently, genetic genealogy tests do not intentionally diagnose obvious disease variants (could CCR5, offered by FTDNA, be considered part of this group?).

The Laboratory Test Improvement Act defines a “laboratory-developed test” as one that uses “analytical methods developed by a laboratory to process a biological specimen, whether at 1 laboratory site or multiple sites, to report a test result to a health care practitioner, a patient, or a consumer; and includes an in vitro diagnostic product that the laboratory has modified, unless such modification requires preclearance or preapproval of such modified in vitro diagnostic product under this Act.”

The Act specifically excludes:
1) “the processing of a biological specimen to: a) determine paternity, b) aid in forensics, or c) conduct research if the result of the test is not reported to a health care provider, a patient, or a consumer;
2) An in vitro diagnostic product; or
3) An analyte specific reagent [defined in the Code of Federal Regulations].”

The Act also states that laboratory-developed tests shall be classified as a “device” under section 201(h) of the FFDCA. Section 201(h) defines device as “an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component, part, or accessory, which is [among other things] intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man…”

Based on the ‘intent’ of the legislation (suggested by Sen. Kennedy’s press release and statements before the Senate) and the definitions contained in the Act, it is unlikely that tests offered for genetic genealogy will fall under the scope of the Laboratory Test Improvement Act.

It is possible that companies offering genetic genealogy testing might be forced to comply with the Laboratory Test Improvement Act in the future if the scope of their sequencing grows. As whole-genome sequencing becomes cheaper and cheaper, companies will want to offer many more options to their customers, including disease gene variants. After all, unless the mutation is spontaneous we inherited the variant from our ancestors. Already the media is filled with stories of whole families that possess a dangerous allele and are submitting their DNA for testing. The line between testing for genealogical purposes and for purely genetic purposes is fading. That being said, the Laboratory Test Improvement Act clearly does not forbid any of the testing described. New “homebrew” tests will be allowed to come onto the market without FDA review provided they a warning that they have not been FDA-cleared or –approved. Perhaps this could benefit consumers by preventing testing by companies who offer sub-par services.

The Text of the proposed legislation is available here. Here is a blog discussion of the legislation and a news article that mentions Genelex, a company that offers both genetic genealogy tests and disease gene screening.

What are your opinions on this topic?

The Daily American Newspaper in Somerset, Pennsylvania, recently highlighted a family surname study being conducted through a local forensics company.  The Eustace/Eustis/Eustice surname Y Chromosome DNA study began in July 2006 and according to the news article the project has tested 80 men in eight countries, a remarkable number.

Ron Eustice, one of the leaders of the study and editor of the Eustice Families Post newsletter emphasizes the importance of DNA to his genealogical research:

“Most family historians have spent countless hours poring over genealogical records, trying to connect the dots.  DNA testing is rapidly establishing itself as the newest and perhaps most reliable tool in the field of family history research. I believe that including DNA evidence is an essential part of family history research.”

Gaskin Forensics in Rockwood, Pennsylvania, collected and tested the individuals in the surname study.  The company provides a wide variety of forensic DNA testing in addition to testing the paternal or maternal relationship between two or more individuals.

Argus BioSciences, located in Belmont, California, is an up-and-coming company offering DNA sequencing for the study of genetic genealogy. Founded in 2003 by Dr. David Whyte, the company offers mtDNA sequencing and haplotype determination.

Although Argus is currently (as of March 2007) offering only mtDNA testing, all products are being offered at a greatly reduced rate. Sequencing of the hypervariable region (which includes HVR1-3) is offered for only $125.00 (regularly $149). You can compare this price to those offered by other companies in my DNA testing company comparison chart. Additionally, Argus is offering complete sequencing of the entire mitochondrial genome (16, 569 bases) for $345 (regularly $695). The company will also accept four monthly payments of $95 to pay for a full sequencing (to inquire, contact Argus at info@argusbio.com). Currently only one other company (Family Tree DNA) offers complete mtDNA sequencing as a regular product.

To expand its services, Argus recently announced that it has teamed up with Marligen Biosciences to offer Y-chromosome haplotyping in the near future.

Interestingly, Argus offers a variety of non-genealogical DNA sequencing (can any DNA sequencing be considered non-genealogical, I wonder?), including cancer tissue screening and sequencing of your gene of interest. Click here to see a list of the genes that they sequence. The company does require that there be 30 samples in a batch to initiate sequencing. To inquire about prices and genes sequenced, contact Argus.

Mitochondrial sequencing results from the company include detailed sequencing results with lengthy analysis of each polymorphism detected, an extensive phylogenetic tree of global mitochondrial DNA, and an mtDNA migration map.

The website has a lengthy FAQ page as well as an informational page examining the use of mitochondrial DNA for genealogical purposes.

The last time I counted there are at least 21 unique companies offering DNA testing for genealogical purposes, either Y-chromosome, mtDNA, or autosomal testing (see the Sidebar to the right for a listing).  To get a clearer picture of what each company offers I created a master list of every company and the services they offer.  See here.

While compiling the list I also gathered information about the markers that each Y-chromosome test analyzed.  See here.  There are of course the standard markers offered by most companies as well as the markers offered by only a single company.  What company have you been tested by?