Thursday, April 16, 2015

Origin and Spread of Cystic Fibrosis

Cystic Fibrosis has an interesting story in Western Europe.  While changes in the 7q31.2 chromosome 7 (CFTR) have occurred independently at low frequencies, two separate haplogroups have spun out identifiable Cystic Fibrosis.  Of these, only one mutation, the ΔF508 deletion, of haplotype 1 has a frequency greater than 1% and causes about 2/3 of the total cases, concentrated mostly in Europe. 

The ΔF508 mutation causes around 66% of CF cases and is estimated to have arrived in Western Europe around 3,000 B.C. based on a phylogenetic timescale by (Busch, 1990).  More recently, Phillip Farrell and the University of Wisconsin have being doing genetic analysis on Iron Age Celts from the La Tene Period and Bronze Age individuals from the Danube.  They have a working hypothesis that ΔF508 entered Europe with large scale migrations in the Iron Age or thereabouts.  Some of the reasoning behind their origin hypothesis is very intriguing (more on that).

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is a gate keeping gene in the cell membrane that we all have.  It lets good things in, keeps bad things out.  It allows bad things to exit the cell and it enables the repair of damaged DNA.  Since people are largely juice and other stuff, defective 'shuttle valve' machinery in a cell membrane is damning in a homozygote.

At some point in the Pleistocene, a population with the CFTR gene in the lower branch (below) had successive mutations that dramatically increased in frequency at some time during the Holocene, and it has since descended in many Western Caucasians leaving a bread-crumb trail that makes it an interesting subject for population geneticists.

Figure 3.
Maximum-likelihood tree of allele frequencies of five loci (IVS6aGATT, IVS8CA, T854, IVS17bTA and TUB20) among normal chromosomes, from worldwide populations, and among CF chromosomes (ΔF508, G542X, N1303K, G551D and W1282X chromosomes). The inset shows an enlarged maximum-likelihood tree of allele frequencies of two loci (IVS8CA and IVS17bTA) among ΔF508 chromosomes in different European populations (Fbas = Basque; Fbri = British; Fbul = Bulgarian; Fcze = Czech; Fden = Danish; Ffin = Finnish; Ffra = French; Fger = German; Fhun = Hungarian; Fire = Irish; Fita = Italian; Fslo = Slovakian; Fspa = Spanish; Fswe = Swedish). Bars show the scale in genetic-distance units. Several trees have been built, using either other methods (e.g., Nei-Kimura distance and the neighbor-joining algorithm) or different sets of chromosomes. In all cases, results are similar.  (Mateu et al, 2007)
Like sickle cell anemia or the Rhesus D deletion, it is a usually a single deletion or mutation that traditionally caused infertility and death to European homozygotes (two copies), but is theorized to have survived culling pressure among heterozygotes, possibly due to typhoid (salmonella) resistance (which has been partially demonstrated).

A more recent hypothesis by the Wisconsin team believes that recessive CFTR mutations exponentiated as a response to arsenic and lead poisoning of Iron Age metal workers, the Celts of which have shown to be 1/30 carriers, similar to moderns.  Bronze Age Danubians, on the other hand, have not shown any CFTR mutations so far (however I would counter that their hypothesis actually corresponds to a spike in the Early Bronze Age or earlier otherwise its impossible to be 1/30 in the Iron Age).*

A paper in 2000 placed the origin of main culprit, ΔF508, in the Iranian plateau then spreading to Atlantic Europe and Baluchistan via a population movements.  In Europe it forms a very sharp cline in the NW.  It's lower frequency towards the SE of Europe is thought to lie with genetic heterogeneity, whereas towards the NW populations become increasingly homogeneous with much higher rates of the damaged Asiatic CFTR.  
"The hypothesis proposed here is that the original founder ΔF508 mutation giving rise to cystic fibrosis occurred in those inhabiting the Iranian Plateau and travelled from there eventually to Europe in the first wave of emigrants. Their descendants moved to the area of Baluchistan bringing the mutation with them. During the last 150 years, further migration has occurred into the Gulf Region and the ΔF508 mutation has joined the pool of CF mutations that are common in this region. "  (Dawson & Frossard, 2000)

The hypothesis goes that haplogroup 1 of CF is likely a one time hiccup that has left a phylogenetic bread crumb trail in its child populations.  As such, when looking at an identical CFTR, a population with little or no CF mutations may be viewed as harboring a native state, this might be Southern Iran. In this frame, a large component of European, Baluch and Berber ancestry could be traced to Northern Iran in recent prehistory, but the opposite can not be true.  (Dawson & Frossard, 2000)
This logic seems to have largely been agreeable with Mateu et al, but criticized the zeroing in on a geographic location.  (Mateu et al, 2007)

You can see above where ΔF508 breaks out into microsatellites (IVS8CA and IVS17bTA) and where Europeans are broken out with Basques and Finns being most distant from each other within a given timescale.  With the exception of Bulgaria, it would appear to have entered Europe from the Southwest if I'm reading correctly(?).  Northwest Europeans have the highest frequency of CF and the peak frequency is among Norwegians followed by Atlantids.   Another survey on the European Union found it most frequent in Ireland.  (Farrell, 2007) 

Another fascinating point worth noting, is that the CFTR gene in these West Asian populations (European, Berber, Baluch), in which the vessel CF haplotype occurs, is more directly related to those of North East Asia, particularly Yakuts, than they are to the other CFTRs in the West.  This would indicate the parent haplogroup responsible for G543X, N1303K and ΔF508 originated in Northeast Asia or Siberia.  I've talked a little about Lake Baikal and Sakha regions and early Holocene population movements previously [here].  This would also probably lend support for the idea that it only began exponentiating after arriving in SW Asia and not Siberia.

It is also interesting to note, that CF roughly correlates to the frequency of Haplogroup H* among Caucasians.  This is true among Basque, Baluch, Norwegians, Northern Italians, Berbers and Finno-Russians.  In Caucasians where H is low or absent, CF is similarly absent.
Table 2 [below] is the continental distribution.  South African and Australian whites comprise the majority in those continents, except for North Africans with Berber ancestry.   3120+1G->A is a separate mutation found in Greeks, Arabs and African Americans constituting less than 1%.  Along with three other CF haplotypes, it has failed classification in either of the two identified CFTR haplogroups with CF.


I'll get to the point now, whatever that is:

-Cystic fibrosis is caused by natural, deleterious mutations.  The modified dog-leg haplotype of the first figure appears to have been under recent and heavy selection among Europeans.
-It may have originated in Iran and spread to North Africa and Europe.
-Chronic exposure to heavy metals (arsenic, lead, lead salt), Typhoid outbreaks (salmonella) or high intake levels of to toxic plants (henbane, mushrooms, poison berry) have kept Cystic Fibrosis from diminishing.
-Cystic Fibrosis may have entered Europe with a population movement sometime between the Neolithic and the Metal Age and exponentiated dramatically with founder effects from the South to the North.

Early Neolithic Europeans and their hunter predecessors certainly had Cystic Fibrosis at low frequencies, but at the wrong end of the haplotree.  Whenever Cystic Fibrosis became became prevalent, it expanded rapidly with a small founder population that populated many different regions.  Chalcolithic?




See also:
CFTR mutation analysis and haplotype associations in CF patients

Online Mendelian Inheritance in Man
http://omim.org/  >> Cystic fibrosis 
Also, Cystic Fibrosis Mutation Database

University of Wisconsin >Cystic Fibrosis research   

 

6 comments:

  1. I may not be able to respond to comments very quickly. FYI

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  2. Excellent post, cheers!

    Also, I wonder if livestock domestication led to an increase in CF transmission among genetically susceptible populations.

    http://www.bbsrc.ac.uk/documents/amr-making-the-leap-pdf/

    Making the leap: Cross-species transmission of Staphylococcus aureus
    "Research led by Professor Ross Fitzgerald from the Roslin Institute at the University of Edinburgh, and others, has found that S. aureus has made numerous leaps between host species; from humans to animals such as dairy cattle and pigs and vice versa. In particular, a 2013 study by Professor Fitzgerald and colleagues showed that a bovine strain called CC97 had made two separate leaps to humans. “There may be a lot more cross-species transmission than we anticipated,” says Professor Fitzgerald. "

    It seems that the most common HLA haplotype among Europeans, which reaches peak world frequency in the Irish, might have been selected for as it appears to delay the onset of colonization in CF.

    http://intimm.oxfordjournals.org/content/18/11/1585.full.pdf

    The 8.1 ancestral MHC haplotype is associated with delayed onset of colonization in cystic fibrosis
    Abstract
    "Major cause of death in patients with cystic fibrosis (CF) is colonization with Staphylococcus aureus and Pseudomonas aeruginosa. The wide phenotypic variation in CF patients suggests that genes other than the cystic fibrosistransmembrane conductance regulator (CFTR) gene modify the disease. The 8.1 ancestral haplotype (8.1AH) in main histocompatibility complex is associated with alterations of the immune response. To study the influence of carriage of 8.1AH on frequency and onset of colonization in CF patients, DNA samples of 72 CF patients (39 homozygous and 33 heterozygous for DF508) were genotyped for member alleles of the 8.1AH: HLA-DQB1*0201, HLA-DRB1*0301, receptor for advanced glycation end products (AGER) 429C, HSP70-2 1267G (HSP70-2G) and tumor necrosis factor-a (TNF-a) 308A (TNF2). Colonization was verified by regular clinical and bacteriological screening. Frequency of colonization was significantly (P=0.012) lower in the 8.1AH carriers; age, gender and DF508 genotype-adjusted odds ratio to be colonized of the carriers versus non-carriers was 0.112 (0.024–0.520). According to survival analysis, patients with 8.1AH had significantly (P<0.0001) longer colonization-free period compared with non-carriers. Our novel observations demonstrate that the 8.1AH is associated with delayed onset of colonization in CF, presumably by influencing defense mechanisms against infections"

    http://en.wikipedia.org/wiki/HLA_A1-B8_haplotype
    http://en.wikipedia.org/wiki/HLA_A1-B8-DR3-DQ2
    https://en.wikiversity.org/wiki/HLA/A*01:01:01:01
    https://en.wikiversity.org/wiki/HLA/B*08:01:01
    https://en.wikiversity.org/wiki/HLA/DRB1*03:01:01:01

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    Replies
    1. Very interesting. I'll have to read more into this.

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  3. Excellent insight with obvious applications to historical population genetics and the Bell Beaker people in particular.

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  4. Very interesting, I never heard of the metal poisoning effect before.

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