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Weitervererbung Mukoviszidose

Frage
Sehr geehrte Damen und Herren,

ich bin Schüler an einem Gymnasium und schreibe gerade in Biologie eine Klausurersatzleistung über die Krankheit Mukoviszidose.
Bei meiner Recherche über Mukoviszidose habe ich gelesen, dass sie die häufigste tödlich verlaufende angeborene Stoffwechselkrankheit bei hellhäutigen Menschen in Europa und den USA ist.

Mich würde interessieren, warum die Krankheit vor allem bei hellhäutigen Menschen weitervererbt wird?

Über eine zeitnahe Rückmeldung würde ich mich sehr freuen.

Vielen Dank im Voraus für Ihre Bemühungen.
Antwort
Lieber Fragender,

interessante Frage für die Biologie - die vermutlich richtige Antwort lautet "Founder Effekt". Das bedeutet, die häufigste mukoviszidoseauslösende Mutation F508del-CFTR ist bei den Vorfahren der heutigen weisshäutigen Mitteleuropäer entstanden - und bis heute in der Bevölkerung verblieben, man vermutet hierzu, dass heterozygote Genträger eine Vorteil gehabt haben könnten, wenn sie Durchfallerkrankungen bekamen. Daher: entstanden ist F508del-CFTR in grauer Vorzeit bei den Vorfahren heutiger weisshäutiger Europäer (wo immer diese inzwischen auch hingezogen sind), weitergegeben bis in die Jetzt-Zeit wurde F508del-CFTR vermutlich, weil es bei Genträgern zumindest keine Nachteile oder gar leichte Vorteile gab.

Nachgerechnet hat das die Arbeitgruppe um Xavier Estivill in den 90ger Jahren, falls Sie die Quelle recherchieren wollen -diese ist hier: https://pubmed.ncbi.nlm.nih.gov/7920636/

Falls Sie den Artikel nicht lesen können (könnte Paywall sein) hilft eine Universitätsbibliothek. Vorab kopiere Ihnen die wichtigsten Textpassagen hierher (unter den ***).

Beste Grüße und viel Erfolg bei der Biologie-Klausurersatzleistung,
Frauke Stanke

*****
aus: Morral et al. "The origin of the major cystic fibrosis mutation (delta F508) in European populations" Nat Genet. 1994 Jun;7(2):169-75. doi: 10.1038/ng0694-169.

aus der Einleitung / Verfahren und Ziel der Studie:
"The evolution of microsatellites from the ancestral haplotype in which a mutation occurred provides an exceptional resource for the study of the origin and evolution of this mutation. We have previously applied microsatellite markers to analyse the evolution and age of several CF mutations in a limited sample of Spanish CF chromosomes. We present the analysis of DeltaF508 chromosomes from 15 European regions, using three intragenic CFTR microsatellites (IVS8CA, IVS17BTA and IVS17BCA). Our study reveals the distribution of these CF chromosomes
throughout Europe and provides, by studying the microsatellite variation, information on the evolution and age of the DeltaF508 mutation. "

Aus dem Ergebnisteil:

" The evolution of ~F508 haplotypes can be traced from
the original 23-31-13 through a maximum parsimony
analysis20 (Fig. 1 ). Since the number of haplotypes that
have evolved from the ancestral chromosome on which
the ~F508 arose should be proportional to the time needed
to give rise to them, an estimation of the rate at which this
variation occurred may be used to calculate the time
needed for the variability observed. No new alleles at any
of the three loci were detected in about 3,000 meioses
studied for each locus. Based on these data, the maximum
mutation rate, with a confidence level of95o/o, comes to
3.3 X I0- 4
/locus/gamete. Using this rate, the minimum
number of generations which has passed since ~F508
occurred, calculated using a Poisson distribution, is 2,627.
Assuming a low value of20 years for generation time21 , the
~F508 mutation arose 52,000 years ago, or probably
more. "


"A comparison of microsatellite haplotype
frequencies for ~F508 and normal chromosomes shows
that the genetic distance between these two groups is high.
The maximum likelihood20 representation of haplotype
frequencies of ~F508 and normal chromosomes from
European populations, shows a clear cut distinction
between CF and normal chromosomes (data not shown).
This separation signifies a much older diversification
between these two groups from that existing among normal
chromosomes of European populations, and suggests
that the ~F508 mutation did not arise in the present
European genetic background, but in a different one,
which was ancestral to the population that later spread it
throughout Europe. "

Aus der Diskussion der Daten durch die Autoren:

" Since DeltaF508 arose a minimum of 52,000 years ago, it is
possible that this mutation, associated with the four most
common haplotypes, was present in the genetic
background of the morphological modern humans that
entered Europe with the Upper Paleolithic cultures about
40,000 years ago.
"
"The maintenance of the gene frequency of DeltaF508 at the
present high figure of 1.4% (of the 2% of chromosomes
which carry a CF mutation, 70% carry DeltaF508) suggests
that there is a carrier advantage at the individual, gamete
or gene level."

"
In conclusion, we propose that the DeltaF508 mutation
arose at least 52,000 years ago in a population genetically
distinct from the present European population. The
mutation was introduced to Europe at different periods.
It was first spread during the Paleolithic period associated
with the ancestral haplotype 23-31-13, but also with
haplotypes 17-31-13, 17-32-13, and 23-32-13. This
agrees with the fact that Basques, who are thought to be a
Paleolithic population30, have a high frequency of DeltaF508
( 88% )31 , with most chromosomes ( 66%) associated with
haplotype 23-31-13. Further expansions were responsible
for the pattern of haplotypes observed in Central and
Northern Europe, where L1F508 is mainly associated with
haplotypes 17-31-13 and 17-32-13. This later
introduction of DeltaF508 increased the frequency of the
mutation in these regions. According to the calculated age
and mostly to the demographic impact of the expansion,
it is possible that these migrations took place during the
Neolithic period, and included the so called Linear Pottery
culture (LBK, Linienbandkeramik). The expansion of
LBK seems to agree with the wave of advance model
postulated by Ammerman and Cavalli-Sforza, with a
significant population growth and a subsequent genetic
replacement in the area of Central Europe. "
07.03.2022
Die Antwort wurde erstellt von: Dr. Frauke Stanke