Gene Expression

Weird finding:

A mutation in a gene commonly associated with deafness can play an important part in improving wound healing, a scientist told the annual conference of the European Society of Human Genetics in Amsterdam, The Netherlands, today (Monday 8 May 2006). Dr. Stella Man, from the Institute of Cell and Molecular Sciences, Queen Mary’s University, London, UK, said that the discovery may have implications for the treatment of a wide range of wounds, including post-surgery.

Professor Kelsell was the first to describe the link between Cx26 mutations and deafness in 1997. “Since many people carry this mutation”, Dr. Man said, “and people who have just one such mutation are not deaf, we felt that there might be some evolutionary advantage to it, so we decided to investigate how the mutation affected the ability of cells to communicate with each other in the epidermis where Cx26 is also expressed.”

I guess they are positing heterozygote advantage. The only thing is one assumes that selection for heterozygosity would be a) strong b) recent, because being deaf is really maladaptive, and modifier genes would have evolved to mask that trait given enough time. If this is a standard Mendelian trait, than the frequency of the homozygotes (deaf) in the population would be q2, where p = wild type, and q = mutant. If a pq combination is more fit than either pp or qq, its increase in frequency would be buffered by the fact that as q increases (ergo, the % who are pq increases) the number who are qq also increases. In a situation where you want to maximize pq, the heterozygote, and the homozygotes have equal fitness, you’d have p = .5 and q=.5, so that the frequency of the heterozygotes would be 2pq, or 50%. But, you’d have 25% who are qq, which is not good, since we know they are maladptive….

Anyway, JP is at the conference where this was presented, so perhaps he’ll have more details soon.

Update: For overdominance/heterozygote advantage….

pq (heterozygote) = 1
pp (homozygote = 1 – s1
qq (homozygote) = 1- s2

Where s = selection coefficient

Equilibrium frequency of p is = s2 / ( s1 + s2)

Assume that pp (wild type) has a fitness of 0.95 (ergo, s1 = -0.05) and qq (deafness) has a fitness of 0.5 (ergo, s2 = -0.5). You get a frequency of p as 91%, so that heterozygotes are 16.5% of the population.

So, this paper is of interest, High carrier frequency of the 35delG deafness mutation in European populations. Genetic Analysis Consortium of GJB2 35delG:

Congenital deafness accounts for about 1 in 1000 infants and approximately 80% of cases are inherited as an autosomal recessive trait. Recently, it has been demonstrated that connexin 26 (GJB2) gene is a major gene for congenital sensorineural deafness. A single mutation (named 35delG) was found in most recessive families and sporadic cases of congenital deafness, among Caucasoids, with relative frequencies ranging from 28% to 63%. We present here the analysis of the 35delG mutation in 3270 random controls from 17 European countries. We have detected a carrier frequency for 35delG of 1 in 35 in southern Europe and 1 in 79 in central and northern Europe. In addition, 35delG was detected in five out of 376 Jewish subjects of different origin, but was absent in other non-European populations. The study suggests either a single origin for 35delG somewhere in Europe or in the Middle East, and the possible presence of a carrier advantage together with a founder effect. The 35delG carrier frequency of 1 in 51 in the overall European population clearly indicates that this genetic alteration is a major mutation for autosomal recessive deafness in Caucasoids. This finding should facilitate diagnosis of congenital deafness and allow early treatment of the affected subjects.

I doubt it is at equilibrium….

Related: Hardy-Weinberg Equilibrium.

Comments

  1. #1 RPM
    May 8, 2006

    The only thing is one assumes that selection for heterozygosity would be a) strong b) recent, because being deaf is really maladaptive, and modifier genes would have evolved to mask that trait given enough time.

    Is deafness as maladaptive as sickle cell anemia? Didn’t the sickle cell phenotype used to confer a fitness of zero (homozygotes did not survive to reproductive age)? I believe modern medicine has changed that, but only in the past century. I wonder how the fitness advantage conferred upon Cx26 heterozygotes (over wild type individuals) compares to that of sickle cell heterozygotes.

    I also want to see some allele frequencies. “Many people” doesn’t mean much to me. Could this be a case of mutation selection balance? I’ve heard arguments that the cystic fibrosis allele is maintained by overdominance, but the frequency of the mutant allele is low enough that it can be explained by new mutations entering the population (especially considering that selection against the allele only occurs in homozygotes).

  2. #2 Max Kaehn
    May 8, 2006

    Deafness may be more maladaptive in literate cultures where gesture isn’t as important. I’ve heard that there are tribes in Africa where going deaf isn’t that big a deal because so much can be expressed through gesture.

  3. #3 razib
    May 8, 2006

    please note, i think ‘maladaptive’ was too strong a word. rather, i’m thinking a fitness reduction.

    re: malaria, rpm, we are talking mondo selection coefficients over the past 5,000 years.

  4. #4 gcochran
    May 8, 2006

    Gene frequency of the standard connexin-26 mutation (35delG) in southern Europe is roughly 1.5%, frequency among Ashkenazi Jews (3/4 a Middle Eastern mutation, 1/4 35delG) is about 2.5 %.
    “maladaptive” is way too weak a work. Profound congenital deafness, in the old days, was a fate worse than death.

    As for the idea that lethal and effectively lethal mutations like CF and connexin-26 deafness could reach such high frequencies in large mixed populations – not so.
    Check the numbers. They’re both mostly a single allele: you won’t see that from continuing mutation.

  5. #5 razib
    May 9, 2006

    I’ve heard arguments that the cystic fibrosis allele is maintained by overdominance, but the frequency of the mutant allele is low enough that it can be explained by new mutations entering the population (especially considering that selection against the allele only occurs in homozygotes).

    btw, wouldn’t this imply that a caucasian specific mutational hotspot?

  6. #6 RPM
    May 9, 2006

    I don’t know enough about the molecular genetics of CFTR. It’s possible that the wild-type haplotypes segregating in european populations are predisposed to mutate to the CF allele. There are multiple mutant alleles, so it’s not like they have a single origin.

    An allele at low frequencies will be found almost entirely in heterozygotes, so selection will only be able to act on the few homozygotes. Additionally, because the majority of alleles are wt, the probability of mutating from wt to mutant is greater than from mutant to wt. I’ve seen a simple analysis which shows that the frequency of mutant CF alleles is consistent with mutation selection balance. I’m not sure how accurate the allele frequencies were, however.

  7. #7 razib
    May 9, 2006

    i’ve seen 1 out of 25 carrier status in caucasians. seems high to be due to mutation.

  8. #8 gcochran
    May 9, 2006

    RPM: no. for a lethal recessive, the equilibrium gene frequency is the square root of the mutation rate. Since the gene frequency is over 2% in Europeans, that would imply a mutation rate of 4 x 10-4, which is implausibly high. In addition, it’s a hell of a lot rarer in non-Europeans. On top of that, a single allele, delta-F508, account for the majority of mutations in most European populations.
    It’s selection. For that matter, selection is the cause of a lot of less-common genetic diseases, such as hemochromatosis.

    Typically, lethal recessives have slight negative effects in heterozygotes as well, which would further reduce the equilibrium gene frequency: judging from Drosophola, the typical recessive lethal lowers heterozygote fitness by 2%.

    You might also note that if the normal gene frequency for a recesive lethal was 2%, then the chance of _not_ having _some_ lethal genetic condition (assuming 25000 genes) would be about 1 in 20,000. We’d all be dead.

  9. #9 gcochran
    May 9, 2006

    Correction: hemochromatosis is fairly common. But it’s impact on reproductive fitnewss is fairly small. I tend to think in terms of the individual fitness decrease multiplied by the frequency of the condition.

  10. #10 JP
    May 9, 2006

    Anyway, JP is at the conference where this was presented, so perhaps he’ll have more details soon.

    sorry to disappoint; I was in a different talk at the time. but here’s the abstract from the conference book:

    A large proportion of recessive non-syndromic hearing loss is due to mutations in the GJB2 gene encoding connexin 26 (Cx26), a component of the gap junction. Within different ethnic groups, there are specific common recessive mutations each with a carrier frequency between 1-3% suggesting a possibility of heterozygous advantage. Indeed, carriers of the R143W-GJB2 allele, the most prevalent in the African population, present with a thicker epidermis than non-carriers and in an early in vitro study we have previously demonstrated that human keratinocytes expressing R143W-Cx26 mutant are protected from cell death compared to wild-type Cx26. In our study, we investigated the role of wild-type Cx26 and R143W-Cx26 in epidermal wound healing by focusing on key features of a regenerating epidermis. We show increased migration and proliferation in cells expressing R143W-Cx26 compared to wild-type Cx26 counterpart. In addition, R143W-Cx26 expressing keratinocytes form a significantly thicker epidermis in an organotypic co-culture skin model. We also demonstrate that cells expressing this mutant Cx26 are significantly less susceptible to cellular invasion by the enteric pathogen Shigella flexneri. These studies demonstrate the advantageious effect of R143W-Cx26 in epithelia by enhancemenent of cellular aspects of epithelial wound healing and an inhibitory effect on bacterial invasion. These data suggest that loss of Cx26 expression either through GJB26 mutation or topical inhibition may have beneficial effects on the rate of wound repair and protection from infection

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