Recently in Genetics Category

Here's a post that will increase my spam count:

Canadian investigators found that sildenafil (Viagra; Pfizer) maintained contractile function of the heart in a mouse model (mdx) of Duchenne muscular dystrophy. The results of the study, which was not supported by Pfizer, were published in the latest issue of PNAS and picked up in wincingly cute fashion by Forbes ("New Use Pops up for Viagra"). Sildenafil, a selective inhibitor of cGMP-specific phosphodiesterase 5, was assessed in the mdx model, because the investigators found that DMD's late cardiomyopathy may be preceded by defective formation of cGMP.

Image: iStockPhoto.

From the NEJM: after sickle-cell anemia, α- and β-thalassemias, and G6PD deficiency.

According to Fox News, the FBI has shortened its list of suspects who perpetrated the 2001 "anthrax letter attacks" to about 4, and 3 of those suspects are scientists with links to the bioweapons research facility at Fort Detrick, Maryland (USAMRIID). The 3 USAMRIID suspects are described as a former deputy commander, a leading "anthrax" scientist, and a microbiologist, whose writing samples have been obtained by the FBI. The current short list apparently does not include former "person of interest" and USAMRIID scientist Steven Hatfill.

It is presently believed that the attacks were perpetrated by placing a "weaponized" powder version of Bacillus anthracis, which was taken from Fort Detrick, inside the mailed letters. Fox News obtained an e-mail (the date of which was not provided), in which USAMRIID scientists discussed how the B. anthracis powder that was provided by the FBI for analysis was "nearly identical" to that made by a colleague, whose name was deleted from the e-mail.

The B. anthracis strain identified in the 2001 anthrax attacks belongs to the Ames strain, and its genotype (62) indicates that it was originally obtained from a dead cow in Texas in 1981. According to leading B. anthracis investigators, the Ames strain is now apparently rare in nature but is in widespread use in laboratories. Consequently it is believed that the strain of the 2001 anthrax attacks was obtained from a laboratory involved in B. anthracis study.

The big trick in the investigation has been to narrow the attack strain to a single laboratory—a very big trick, since B. anthracis generally and the Ames strain specifically are highly genetically conserved. Just last year, B. anthracis expert Paul Keim and colleagues at Northern Arizona University published their identification of 6 single nucleotide polymorphisms* (SNPs) that merely distinguish the Ames strain from other B. anthracis strains, including close genetic relatives.

However, in a March 18 letter to the Letters in Applied Microbiology, the same investigators reported that they were able to identify 6 distinct genotypes of a single B. anthracis clone (obtained from a 2005 outbreak in South Dakota) by using 4 highly mutable single nucleotide repeat (SNR) markers. SNRs are variable-number tandem repeats in the DNA sequence that exhibit very high mutation rates. The authors concluded, "SNR markers are powerful tools for detailed tracking of natural B. anthracis outbreaks and could also prove useful in forensic investigations."

It seems logical that investigators would be using (or have used) SNR markers in an attempt to subtype various Ames strain isolates from different laboratories.

*Six SNPs were highly specific for the Ames strain: 4 were on the chromosome; 1 was on the pX01 plasmid; and 1 was on the pX02 plasmid.

Another question prompted by the case of Hannah Poling is whether children with autistic features should be screened for mitochondrial disorders. When Hannah exhibited autistic regression after a series of vaccinations at the age of 19 months, she was ultimately found to demonstrate mitochondrial dysfunction (Poling JS et al. J Child Neurol. 2006;21:170-172). The authors (including Hannah's neurologist father) suggested that "oxidative stresses from immune activation" may lead to autistic regression in children with compromised mitochondrial function.

Poling and company then conducted a follow-up, retrospective study of patients with autism, who had not been diagnosed with metabolic disorders. They found that AST levels were elevated in 38% (vs 15% in age-matched controls; P < .0001), and that serum creatinine was elevated in 47%. The authors concluded that "further metabolic evaluation is indicated in autistic patients and that defects of oxidative phosphorylation might be prevalent."

The recommendation to evaluate autistic children metabolically was made by Pons et al (J Pediatr. 2004;144:81-85), who described several autistic children with the mitochondrial DNA mutation that typically causes MELAS.* These authors concluded that "autistic features may be the expression of mitochondrial dysfunction in a developing brain" and that "analysis of mitochondrial metabolism should be considered in autistic patients with associated neurologic findings or evidence of maternal transmission."

However, in a review article published that same year (Lerman-Sagie T et al. J Child Neurol. 2004;19:397-381), investigators at Tel Aviv University concluded that "mitochondrial diseases are probably a rare and insignificant case of pure autism" and further advised that care should be taken when ascribing autism to identified mitochondrial abnormalities. Detection of mitochondrial dysfunction may be the result of laboratory shortcomings, or mitochondrial dysfunction may be unrelated to clinically manifest autism.

The following year, a population-based Portugese study of autistic school children (Oliveira G et al. Dev Med Child Neurol. 2005;47;185-189) found elevated plasma lactate levels in approximately 20% of those tested and mitochondrial dysfunction in a surprisingly high 7%. Unfortunately there were no distinguishing features, such as clinical phenotype or family history, to aid the differentiation between autistic children with mitochondrial dysfunction and those without.  

The bulk of the data to date (and there is little "bulk") indicate that the likelihood of identifying mitochondrial dysfunction in an autistic child is low, but probably not insignificant. Also Oliveria and colleagues remind us that the tissue distribution of mutant mitochondrial DNA is variable and could explain possible false-negative evaluations for mitochondrial dysfunction in cases of autism.

*MELAS = mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke.

A letter in the latest issue of the NEJM indicates that the number of neonates identified with cystic fibrosis (CF) through neonatal screening declined substantially during the 4-year period from 2003 to 2006 in Massachusetts and was associated with a significant decrease in the number of infants with the most common CF-related genotype, ∆F508/∆F508.

The authors, from the New England Newborn Screening Program, observed an expected number of infants with CF from 1999 to 2002; however, in 2003, infants identified with the ∆F508/∆F508 genotype declined significantly, and this decline was maintained during the next 4 years.

The authors conjecture that the gradual uptake of preconception and prenatal screening to identify CF carriers among the general population since 2001 has resulted in fewer births of children with recognized CF-related genotypes. But they advise that the reduced incidence of known CF genotypes will lower the predictive value of newborn screening for CF.

Photo: iStockPhoto

A recent article authored by investigators at the University of Utah features an all-time favorite pastime: genealogic digging. The authors examined 2 large kindreds, one in Utah and one in New York, that share an identical autosomal-dominant (AD) deletion mutation, c.426_427delAT, which determines an attenuated form of familial adenomatous polyposis (FAP). FAP and its attenuated forms (AFAP) are associated with substantially increased risks of colonic polyps and colorectal cancer, FAP moreso than AFAP, but phenotypic variance appears to be considerable, particularly in individuals with the attenuated conditions.

 

By using genealogic records at the massively stocked LDS* library and matching surnames between the 2 pedigrees, the investigators identified a common ancestral couple who emigrated from England to America in the early 1600s: George Frye and his nameless wife, aka Mrs. George Frye. The interesting thing about this couple is that the c.426_427delAT mutation appears to have spontaneously originated with one of them, because it has not been identified in England or elsewhere in Europe, according to the authors.

 

The big question the article generates is How many Americans currently alive have inherited the original deletion mutation? The authors indicate that genealogic data are presently not sufficient to identify the full extent of descendants of the founding couple; however, there are at least 11 other American families with the exact allele haplotype who have been identified in Texas, Nebraska, Washington, Vermont, or Michigan and 2 additional families in Wisconsin with a slightly different genotype, mostly likely due to recombination events. Whether this tally is complete is difficult to know, until all progeny lines from Mr. and Mrs. George Frye have been traced, and genetic analyses of living descendants have been performed. The absence of colorectal cancer in a particular lineage is unlikely to preclude the presence of the mutation, because of substantial phenotypic variance. Among the 2 studied kindreds, approximately 37% of mutation-positive members had fewer than 10 colonic adenomatous polyps, and only approximately 7% of these individuals were diagnosed with colorectal cancer.

 

According to records at familysearch.org and ancestry.com, George Sr. and wife produced at least 4 children, 2 of which, George Frye, Jr, and Elizabeth Frye, passed on their acquired mutations to the New York and Utah families, respectively. Now it is certainly possible, despite the 50% probability of passing on the AD mutation, that the 2 other children of the founding couple were also affected and passed on the allele haplotype to their descendents.

 

In any event, it is recorded that George, Jr, had at least 4 children, and that Elizabeth had 9 children. Therefore the minimum probability is that 6 individuals of the third Frye generation (b. circa 1640-1660) carried the mutation, and half of those children passed it onto their children, and so forth (providing that the mutation is not subject to selective pressure, which it does not appear to be). For the sake of further argument, if each couple of each successive generation had 4 children, with 2 of those 4 children acquiring the mutation, then by the thirteenth generation (those individuals b. 1920s-40s), more than 6000 individuals carried the c.426_427delAT mutation. The mutation incidence, in this scenario, is then doubled for the fourteenth generation, at 12,000—which suggests a considerable mountain of genealogic and genetic data to dig through.

 

*Latter-day Saints.