Importanza dello studio dell’evoluzione e della selezione per capire le malattie – Medicina evoluzionistica Cancro: cellule con mutazioni che consentono loro di sopravvivere e riprodursi meglio delle altre. Se non ci fossimo evoluti per evolvere, non avremmo mai avuto il cancro (Greaves, 2000) La medicina evoluzionistica inoltre permette di riconoscere molti sintomi come adattamenti del corpo umano.
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Importanza dello studio dell’evoluzione e della selezione
per capire le malattie – Medicina evoluzionistica
Cancro: cellule con mutazioni che consentono loro di
sopravvivere e riprodursi meglio delle altre.
Se non ci fossimo evoluti per evolvere, non avremmo mai avuto il
cancro (Greaves, 2000)
La medicina evoluzionistica inoltre permette di riconoscere molti
sintomi come adattamenti del corpo umano.
Mismatch disease: la
selezione fa un match
tra uomo e ambiente
Diversità genetica umana:selezione e malattie
• Capire il contributo delle forze selettive che hanno avuto un impatto sul genoma umano
• Studiare la diversità genetica di geni coinvolti nelle relazioni con i patogeni, con l’ambiente e con le risorse alimentari.
• Identificare forme specifiche di selezione per questi geni e loro ruolo sul metabolismo.
Environment,
interact to determine genetic
variation in the modern human
species
Epidemics,Travels
(migration)
Positive selection acts on disease resistance alleles
Severe sepsi and CASP12
Humans that lack CASP12 are less likely to
develop severe sepsi
Within CASP12 gene a SNP (rs497116) causes
a premature stop codone
Mutant allele has increase to 95% frequency
in the human population as a consequence of
positive selection within the last 60-100KY.
Kidney disease
Kidney failure is about 4 times more frequent in
African-Americans than in other Americans.
GWAS identified a strong signal for disease
susceptibility in the APOLI gene (rs73885319 and
rs60910145)
APOLI was already known to lyse and thus protect
against Trypanosoma brucei (sleeping sickness).
Selection for resistance to sleeping sickness has
resulted in the high frequency of variants that
strongly increase risk of developing kidney disease
Role of Malaria in shaping the geneticstructure of Sardinian population
Mortality rate (x1000)
Malaria: Endemica già dai tempi
dei Cartaginesi.
1936-1938: una morbilità di
38.655 casi (349, 57 su 10.000);
1941 a Nuoro (383,12 casi su
10.000 abitanti).
Durante la seconda guerra
mondiale aumentò sensibilmente
in tutta l’Italia,
1946 campagnia anti malaria
grazie alla Fondazione Rockfeller
che debellò la malattia con
l’introduzione del DDT (para-
diclorodifeniltricloroetano).
Diffusion of Th-, G6PD-, Fy(a-b-)Correlation with some STRs of NOS gene
Malaria has exerted strong selection pressure on the human
genome by inducing high frequencies of genetic polymorphisms
that protect against malaria infection.
Genetic adaptations to malaria can assume different forms.
Other examples:
ACP1
Red cell acid phosphatase 1 is an enzyme
isolated from several human tissues, and it is
involved in signal transduction pathways
activated by membrane receptos such as the
insuline receptor, T-receptors and others.
It exists in two isoforms.
3 SNPs are identified that affect enzymatic activity. Combination of these SNPs define the common genotypes: ACP*A, ACP*B and ACP*C(enzymatic activity: AA<ab<bb-ac<bc<cc).In Sardinian significant difference among villages.ACP1*C is positively correlated with altitude,ACP1*A shows a negative correlation.ACP1*C presents a negative correlation with malaria: so high ACP activity can decrease membrane rigidityand favour the invasion of the cell by the parassite.
ACP1
TNF
The effect of some SNPs is controversial but they have been associatedwith variuos autoimmune and infectious diseases, including malaria. In Sardegna high frequency of TNF-376° (confers protection frommalaria?)
Tumor necrosis factor is a cytokine that affects lipid
metabolism, coagulation, insuline resistence and
endothelial function and provide a rapid form of host
defense agaist infection.
Correlation between TNF-α levels and BMI and insulin.Possible role of TNF-α in the pathogenesis of type-2 diabetes mellitus and the importance of reducing obesity to prevent elevated levels of the cytokine and related complications.3 SNPs (TNFB+318, TNFA-857, and TNFA-308) and 2 common TNF haplotypes showed significant association with the risk of T1D (P= 5 x 10(-3)-10(-5)) in Korean cohort.
TNF resulted correlated also with sclerosis multiple
ADA - malaria and Diabetes Type I
Adenosine deaminase is a polymorphic enzyme that has an important role in immune functions and in the regulation of intracellular and extracellular concentrations of adenosine and adenosine receptor activity.
The 2(2)/6(1) haplotype may exert a protective action in males but may increase susceptibility to DM1 in females: OR = 0.398, 95% CI 0.16-0.96 for males, and OR = 2.31, 95% CI 1.32-4.06 for females
recently observed that Type 1 Diabetes (T1D) in Sardinia is
associated with ADA2 (Saccucci et al., 2010)
In mammals, there are three isoforms: NOS1, NOS2, NOS3. NOS1: widely distributed in specific neurons of the central and peripheral nervous systems. NOS2: first identified in macrophages, it is induced byimmunological and inflammatory stimuli. It is associated withsusceptibility to infections such as malaria, toxoplasmosis, leishmaniosis, trypanosomosis, and schistosomosis (Rivero, 2006). NOS3: expressed in the vascular endothelium and associated with incidence of hypertension (Levy et al., 2009; Rabbani et al., 2011).
Correlation between NOS STRs and Malaria
Association with complex disease as Parkinson’s disease (Lo et al., 2002), schizophrenia (Tang et al., 2008), or atherosclerosis.
allele (CCTTT)9 in the promoter region of NOS2 could be a protective factor against malaria infection. The highest frequency can be observed in Sarrabus (0.087) and in Trexenta (0.063), (values ofmortality for malaria 80% and 40% respectively, while in the rest of Sardinia average values are around 30%).
Highly significant correlation for STR (TGGA) of NOS2 gene (P-value: 0.016) has been found, while values near to significance have been obtained for markers (TAT) and (TTCT) of NOS1 gene and (AAAAG) of the adjacent region of gene NOS1 (P-value=0.063, 0.068, and 0.058).
These results may suggest that the selective effect of malaria has been brought not only by the prevalence of thalassemic trait but also by selection of NOS1 gene alleles in correlation to NO overproduction as protective factor(Piras et al., 2010).
NOS and diabetes
Nitric oxide (NO) is produced by diverse sources including pancreatic b-cells.A large number of studies have provided evidence foran involvement of NOS2 in b-cell degeneration duringthe process of type 1 DM (Cnop et al. 2005)The presence of NOS1 and NOS3 in pancreatic b-cells and physiological roles of cNOS-derived NO, such as modulation of insulin secretion and protection of b-cells from apoptosis, are suggested It is highly possible that the deregulation ofcNOS-derived NO production or metabolism is involvedin the onset and development of type 2 DM
Relazione Gene-ambiente
geni NAT (arilamina N-acetiltransferasi)
• I due geni giocano un ruolo protettore importante nella detossificazione di xenobiotici per acetilazione.
• Biotransformano molti agenti tossici e cancerogeni.
• NAT1 e NAT2 enzimi intra-cellulari, cellule del fegato, dell’intestino, dell’uretere e della vescica.
NAT1: bassa diversità nucleotidica in tutte populazioni.