Population Genetics and Disease Susceptibility: Characterization of Central European Haplogroups By mtDNA Gene Mutations, Correlation with D Loop Variants and Association With Disease

Abstract

Mitochondrial (mt)DNA haplogroups in a German control group (n = 67) were characterized by screening mitochondrial coding regions encompassing most of the ND, tRNA and cyt b genes. We used a PCR-SSCP screening approach followed by direct sequencing of polymorphic mtDNA fragments. Five major mtDNA lineages, diverging in at least nine different haplogroups, could be defined by characteristic polymorphic sites in mitochondrial genes. Additional sequencing of two hypervariable segments (HVS-I and II) of the non-coding displacement (D) loop in all control subjects revealed that certain D loop variants were strongly correlated with lineages and haplogroups, while others represented hotspots occurring frequently in different haplogroups. The existence of identified lineages and haplogroups received support from data in the literature, obtained by use of different approaches. Subsequently, we investigated four disease groups for association with these haplogroups: (i) LHON patients (n = 55) carrying at least one of the primary/intermediate LHON mutations at nt 3460, 11778, 14484 and/or 15257; (ii) patients suffering from Wolfram or DIDMOAD syndrome (n = 8); (iii) MELAS patients (n = 9); (iv) a group of children, who died from 'sudden infant death syndrome' (SIDS) (n = 9). The distribution patterns among the haplogroups of the disease groups (LHON, DIDMOAD and SIDS) differed considerably from the control population. LHON and DIDMOAD were significantly under-represented in the most frequent German haplogroup DC, but were concentrated in a mtDNA lineage defined by polymorphisms at nt 4216 + 11251 + 16126. As this lineage diverged into two precisely defined haplogroups, LHON and DIDMOAD could be assigned to the two haplogroups separately. Strikingly, SIDS was often found in association with two rare German haplogroups. MELAS patients were equally distributed among German haplogroups and, moreover, did not reveal any accumulation of specific D loop variants. We conclude that certain European mtDNA haplogroups define a genetic susceptibility basis for various disorders.

Mitochondrial DNA haplogroups: Role in the prevalence and severity of knee osteoarthritis

“…Although the mechanism of this protective effect is unknown, a significant biologic role seems likely. Some controversial associations of haplogroup J with other diseases, such as an increased penetrance of the milder complex I gene mutations associated with Leber's hereditary optic neuropathy (LHON) (22,42), an increased susceptibility to multiple sclerosis (43), and an association of cluster TJ with type 2 diabetes mellitus (28), have been described. Interestingly, haplogroup J has also been associated with a decreased risk of Parkinson's disease (26) and with increased longevity in several European studies (31,32,33).…”

“…Among Europeans, 95% of the population belongs to 1 of 9 haplogroups: H, I, J, K, T, U, V, W, or X. Given the lines of evidence that describe the contribution of mtDNA to cellular physiology, as well as its critical importance for energy production, a number of studies have investigated the association between mtDNA haplogroups and multifactorial diseases (22)(23)(24)(25)(26)(27)(28), mitochondrial diseases (29,30), and aging (31)(32)(33).…”

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

“…It is a matter of debate whether the presence of polymorphisms in the mtDNA or in nuclear genes encoding RC components could modify the effects of a particular mutation on the biosynthesis and electron transfer properties of the RC complexes. In this regard, a genetic modifying role for the mtDNA haplogroup background has often been proposed in the clinical expression of LHON, a maternally-inherited blinding disease that constitutes the most common mitochondrial disorder (Brown et al, 1997;Carelli et al, 1997;Hofmann et al, 1997;Torroni et al, 1997;Brown et al, 2002;Carelli et al, 2006;Yen et al, 2006;Hudson et al, 2007;Carelli et al, 2009). An increased complex I-dependent ROS production and decreased antioxidant defenses have been reportedly…”

Tracing European Founder Lineages in the Near Eastern mtDNA Pool

“…The European populations were analyzed by a modified version of the paleo-climatological model of Gamble (1986Gamble ( , 1999, as described elsewhere (Richards et al 1998a): southeastern Europe-141 Bulgarians, including 30 from the study by Calafell et al (1996), and 92 Romanians from Maramureş (65) and Vrancea (27); eastern Mediterranean-65 Greeks from Thessaloniki, 60 Sarakatsani from northern Greece, and 42 Albanians (Belledi et al 2000); central Mediterranean-49 Italians from Tuscany Torroni et al 1998) and 48 from Rome, 90 Sicilians (42 from Troina and 48 from Trapani), and 115 Sardinians, including 69 from the study by Di Rienzo and Wilson (1991); western Mediterranean-54 Portuguese (Cô rte-Real et al 1996), 71 Spaniards (Cô rte-Real et al 1996, 92 Galicians (Salas et al 1998) (156 Basques from northern Spain, including those from the studies by Bertranpetit et al [1995] and Cô rte-Real et al [1996], were treated separately); Alps-70 Swiss (Pult et al 1994), 49 South Germans from Bavaria , and 99 Austrians (Parson et al 1998); north-central Europe-37 Poles, 83 Czechs, 174 Germans Hofmann et al 1997), and 38 Danes, including 33 from the study by Richards et al (1996); Scandinavia-32 Swedes (Sajantila et al 1996), 231 Norwegians, including 215 from the study by Opdal et al (1998), and 53 Icelanders (Sajantila et al 1995;Richards et al 1996); northwestern Europe-71 French, comprising 47 from northeastern France and 24 from the CEPH database, 100 British (Piercy et al 1993), 92 individuals from Cornwall, including 69 from the study by Richards et al (1996), 92 individuals from Wales , and 101 individuals from western Ireland; northeastern Europe-25 Russians from the northern Caucasus, 36 Chuvash from Chuvashia (Russia), 163 Finns and Karelians, including 133 from the study by Sajantila et al (1995) and 29 from the study by Richards et al (1996), 149 Estonians, including 28 from the study by Sajantila et al (1995) and 20 from the study by Sajantila et al (1996), and 34 Volga-Finns (Sajantila et al 1995)…”