C677T mutation of MTHFR gene

 People with MTHFR mutation have elevated homocysteine levels. 

The mutations can lead to high levels of homocysteine in the blood, which may contribute to several health conditions, including:

• birth anomalies
• glaucoma
• certain mental health conditions
• certain types of cancer

Mutations in the MTHFR gene can affect the body’s ability to process amino acids — namely, homocysteine — which can lead to some adverse health outcomes.

Conditions that researchers have associated with MTHFR gene mutations include:

• homocysteinemia, which is the term for abnormally high levels of homocysteine in the blood or urine
• ataxia, which is a neurological condition that affects coordination
• peripheral neuropathy, which is a neurological condition that damages the nerves
• microcephaly, which is a condition present at birth in which the head is smaller than usual
• scoliosis, which refers to an abnormal curvature of the spine
• anemia, which means that there is a lack of healthy red blood cells in the body
• cardiovascular diseases, such as blood clots, stroke, and heart attack
• mental health conditions, such as depression, schizophrenia, Alzheimer
• behavior disorders, such as attention deficit hyperactivity disorder
• recurrent pregnancy loss
• myocardial infraction

677C>T mutation (rs1801133)  and A1298C>T mutation are the major MTHFR gene mutations that cause these issue. The below map shows the distribution of these mutations world wide. As you can see the mutations values are very high (50+%) among certain Mexican, Tuscans, Bosnian, Czechs, Ukrainian, Norwegian, Swedish, certain Chinese and Japanese population world wide. 

certain American Indian groups had very high percent of these mutations making them high susceptible to the different health conditions.

 Remarkably, the frequency of the 677T in Mexican individuals and particularly in MA people, was the highest worldwide. In contrast, the frequency of the 1298C risk allele in Mexicans was the lowest in the world. In addition, the frequency of 677T allele showed an increasing gradient from northern to southern Mexico in both populations; while the 1298C allele frequency showed the opposite gradient (Fig 3). This finding demonstrates the great ethnic diversity and heterogeneity of the genetic background in the country. Consistent with previous studies [7, 8, 13, 16], our findings suggest that one of the major contributions of the 677T allele in MEZ was the Indian admixture; while, the 1298C allele is mainly derived from European genomes. Some ethnic groups had the highest frequencies in the country for the 677T allele. Mocho, Kaqchiquel, and Chuj, belonging to the Mayan linguistic family inhabiting the SE region, had frequencies >80%, and Mazateco, Mixteco, Zapoteco, Totonaco, and Mazahua from the S and CE regions had frequencies >70% (Fig 1). Notably, some ethnic groups showed particularities; for example, the Seris (N), Pame (CE), and Huave (S) had lower 677T allele frequencies than other groups that co-inhabited the same regions (13% vs. 32–47%; 35% vs. 57–74%; and 33% vs. 59–81%, respectively) (Fig 1). Also, we found seven ethnic groups that were monomorphic for the A allele of the A1298C polymorphism (Seri, Pame, Chuj, Kanjobal, Mocho, Mazahua, and Zapoteco) (Fig 2). In contrast to the 677T allele, the MA groups from the N (32–47%), with the exception of the Seris, had the highest 1298C allele frequencies (11–22%). These findings may reflect the particular features and history of migration and isolation throughout the centuries of each ethnic group, including the 5 Nahuatl groups, where heterogeneity was also observed among them.

Among Jewish, the frequency of the C677T MTHFR mutation in healthy Israeli ethnic groups. The frequency of the mutation was determined in 897 young healthy Jewish and Muslim Arab Israelis of eight different ethnic groups. Marked ethnic differences in the frequency of mutant homozygotes were found, ranging from 2% in Yemenite Jews, 4% in Sephardic Jews, 9% in Oriental Jews, 10% in Muslim Arabs, 16% in North African Jews, and 19% in Ashkenazi Jews. The frequency of mutant homozygotes was significantly higher in Ashkenazi Jews compared to Yemenites Oriental Jews, Sephardic Jews, and Muslim Arabs (χ2 = 12.35 p < 0.001, χ2 = 8.17 p = 0.004, χ2 = 6.04 p = 0.01, χ2 = 6.54 p = 0.01, respectively)

Among Arabs, significant differences in groups such as Lebanon Vs Bahrain are noticed. The C677T mutation was present in 169/408 Lebanese and 30/152 Bahraini participants, giving an overall carrier frequency of 41.4% for Lebanese and 19.7% for Bahraini participants [P < 0.001; odds ratio (OR) = 2.83; 95% confidence interval (CI) 1.81, 4.42]. Of the carriers, 159/408 (38.97%) Lebanese and 26/152 (17.11%) Bahraini carriers were heterozygotes (OR = 3.03; 95% CI 1.92, 5.00), while 10/408 (2.45%) Lebanese and 4/152 (2.63%) Bahraini carriers were in the homozygous state (OR = 1.25; 95% CI 0.39, 4.00) . No difference in the MTHFR C677T mutation frequency was seen with respect to gender.

In Iran, The prevalence of MTHFR (C677T) mutation was 17.9% of which 7.1% had the TT mutant allele in homozygous and 10.8% had CT allele in heterozygous state.

In Turkey, a study showed a genotypic distribution CC: CT: TT = 40.0%: 47.3%: 12.7% in 243 coronary patients. In a Chinese study, the genotypic distribution in 106 patients was CC: CT: TT = 63.8%: 25.7%: 10.5%. In a Tunisian study the genotypic distribution in patients was respectively CC: CT: TT = 42.2%: 38.9%: 18.9%. A Tunisian study of 185 apparently healthy subjects in 2005 showed an allele frequency of 17.8% and a genotypic frequency of 5.4%

Among South Asians, T-allele frequency for C677T mutation of MTHFR gene in the South Indian population (0.10) established by this study is lower compared to UK (0.186) and USA (0.322) and much higher when compared to Sri Lanka (0.049)12 . Similar findings were observed among case-control studies conducted in Mumbai and Pune. This shows certain urban groups in India harbor very high C677T mutations making them susceptible to different health conditions. There is no big study to find out more on these. Given high ANE based risk for this gene no wonder the newer groups who came post MLBA might have these higher risks from the mutations.

One of the Indian studies showed that Women have higher C677T mutations in India than Male. Overall Indian percentage is less compared to other major groups in China, Japan, Mexico, Peru, Italy, Bosnia, Scandinavia, Ukraine etc... However Indian probably harbor more localized such mutations in certain urban places like Pune, Mumbai, Chennai, Delhi etc... which requires more investigation and remedies

That probably shows that the Indian mtDNA has more ANE and UP based origin. However the deep Indian HGs like H and F are probable low on this gene and so low on such risk

G25 Analysis of Indian castes

 Running G25 analysis and Southern castes and some northern ones using Swat samples, pulliyar and kadar for AASI & AASI mixed with UP, Kazakh MLBA and EBA, SIS BA2, Gonur1, Amur river BA, Belgium UP,  Italy Daunian shows a pattern

Belgium UP European HG shows up in some Southern castes and UP Brahmin east 

Udegram IA was an ancient Swat town full of Haplogroup E people. Some Brahmins such as UP Brahmins in East and Southern castes seem to have noticeable amount of it.

Pakistan Saidu Sharief was a Buddhist town which seems to be present high among Baniyas, Rajput and Sarypareen/Kanyakubj brahmins

Iran Shahr E Sokhte BA2 was a group of samples found to be high in present Indian like. It is found high in Velamas, Kammas, UP Brahmin East, Kallars etc..

Pulliyars are a AASI population which is shared high with Nambudris, Chamars and Velamas

Kazakh MLBA shows up high in Brahmins, Bhumihars and Rajput

Pakistan Loebanr is a swat town that had Haplogroup L along with H and others. It is very high amoung Punjabis and Brahmins.

Pakistan Swat valley Katelai is a town full of R2 and H1 people found high among Brahmins and Kallars

Kadars are a forest tribals who seem to have some Asian UP and AASI that match high for Chamars, Kallars etc..

Japan JOMON is HG found widely in India among all groups

Italy Daunian is a Med and EBA mixed people influence found among NW Yavan mixed populations, some Brahmins, Kammas etc.

Iberomaurisians are North African population whose admix found among Rajputs, Brahmins and Kammas

Gonur1 was a BMAc town. Many SOuthern castes have high of Gonur BA and some Rajputs and Brahmins

Kazakh Kumsay EBA is ancient admix found among Bhumihars

China Amur river is a North east asia BA era which is found among groups such as Uttarkhands Brahmins and some Rajpts

Swat Aligrama Historical is found high among some Rajputs and Brahmins

Kadars high part2

Pakistan Aligrama IA is ancient town that has influence in South India among Vellalars, Bunts, Kammas, Velama, Reddy etc..

Timeline of mtDNA in Indian Sub continent

 

Timeline for AMH evolution in South Asia based on genetic, archaeological, climatological and linguistic evidence. Black and grey portions of the arrow represent Pleistocene and Holocene, respectively. Blue sections correspond to periods of climate changes: dryer periods between 35 and 30 ka, Last Glacial Maximum ~18 ka, Younger Dryas ~12 ka and the " 4.2 ka " event. Lineages in red stand for the putative Late Glacial/postglacial genetic influx from West Eurasia; green for migrations from West Eurasia around the Pleistocene/Holocene transition, orange for the Neolithic period and blue for the genetic events in the last 4 ka 

Maternal lineages primarily reflect earlier, pre-Holocene processes, and paternal lineages predominantly episodes within the last 10 ka. In particular, genetic influx from Central Asia in the Bronze Age was strongly male-driven,consistent with the patriarchal, patrilocal and patrilineal social structure attributed to the inferred pastoralist early Indo-European society. This was part of a much wider process of Indo-European expansion, with an ultimate source in the Pontic-Caspian region, which carried closely related Y-chromosome lineages, a smaller fraction of autosomal genome-wide variation and an even smaller fraction of mitogenomes across a vast swathe of Eurasia between 5and 3.5 ka

This result suggests that an ancient western ancestry may have been disguised by further re-expansions ofhaplogroup M in South Asia. Several branches of M(M38, M65, M45, M5b, M5c, M34, M57, M33a) display signals of dispersals from the east and the centre datingt o ~45–35 ka, and M4’67 (which is only separated by asingle mutation from the root of M), with a possible origin in central India, displays an extraordinary multi-branching structure dating to 38.0 [30.1; 46.0] ka, suggesting a major expansion at that time. If we considerthat a root type of M could have survived for ~10,000 yearsafter it arose (as is evident from modern clades within thatage range), it is plausible that re-expansion created a sec-ondary founder effect within M that decreased the overallage estimates. Such a scenario would impact even moreon ρthan ML estimates, which is indeed what we see(Table 1). An expansion 45–35 ka would also fit well with the palaeoenvironmental and archaeological evidence[2, 67, 68], and is further supported by an increment inNeassociated with M across South Asia from ~40 ka(Additional file 1: Figure S1).The next major discernible signal in indigenous lineages begins ~12 ka, at the Pleistocene/Holocene transition.Various star-like clades dating 12–9 ka suggest a rapid ex-pansion across the Subcontinent, namely M6a1a (11.4 ka),M18a (9.2 ka), M30d (12.1 ka), R8b1 (11.6 ka) and U2b2(9.2 ka), all from a southern source; and R30c + 373(12.4 ka), from the west. An increment in Neis also ob-served at this time in the BSP for haplogroup M in thewest and south (Additional file 1: Figure S1).We also see a further increment in the last few millennia.BSPs for M in the west and centre show an increment inthelast2.5ka(Additionalfile1:FigureS1),associated withthe emergence of several subclades in the west (M2a3a +4314, M2a1b, M2c + 1888 + 146, M30a2, M5a3b, M6a1 +5585 + 146 + 1508) and centre (M2a1a1b, M3b, M3a1a,M63, M5a2a2 + 234, M5a3a and M61a + 5294).

West Eurasian mtDNA lineages in South Asia: Multiple dispersals from the northwest since the LGM Prehistoric West Eurasian lineages make up almost 20%of the South Asian genetic pool overall.

The Pakistani Muslim Balochi, Brahui and Makrani

carry ~15% of the Near Eastern/Arabian component

(yellow), which is carried across Europe with the spread

of the Early Neolithic [75, 77]. However, this component

is virtually absent in other South Asians (including

Muslims) except for Jewish groups (supporting previous

mtDNA evidence for little genetic input from Arabia

into Indian Muslim populations [78]

The Pakistani Muslim Balochi, Brahui and Makrani

carry ~15% of the Near Eastern/Arabian component

(yellow), which is carried across Europe with the spread

of the Early Neolithic [75, 77]. However, this component

is virtually absent in other South Asians (including

Muslims) except for Jewish groups (supporting previous

mtDNA evidence for little genetic input from Arabia

into Indian Muslim populations [78]

from  A genetic chronology for the Indian Subcontinent points to heavily sex-biased dispersals Pedro Soares et all

Subcontinent points to heavily

sex-biased dispersals

Deep relation between Indian HG and European mtDNA

Compared to South Asia and NE Asia, The peopling of Europe was more marked by human population expansions and contractions associated with major climatic events. Numerous studies indicate a dramatic population contraction in Palaeolithic Europe during the Last Glacial Maximum (LGM, ~26.6–19 cal kyr BP)

With the onset of the LGM, a population decline is observed in central Europe and human populations associated with the Gravettian technologies (33–25 cal kyr BP) retreated to southern latitudes, to regions in today’s Italy and central/southeastern Europe.  Solutrean lithic tradition rooted in western European Late Gravettian technologies emerged during this period of intense cold called Heinrich 2 Event and following the LGM. 

These earliest European population bottleneck from a Goyet like population during post LGM led to mtDNA H which is now the major mtDNA lineage in Europe. 

The recent re-excavations at Bacho Kiro cave (Bulgaria) by archaeologists from Bulgaria and Germany discovered remains of Homo sapiens dated to ~ 45/ 43,000 calBP (Hublin 2020). Three individuals from the Initial Upper Paleolithic layer and another one (a lovely lady) dating to ~ 37,000 calBP (~ Aurignacian era in Europe) were sequenced (Hajdinjak 2021).

The Goyet IUP lineage came in as a part pre-Bacho Kiro lineage and another branching from a later lineage. The paper by Hajdinjak et al found that IUP Bacho Kiro Cave individuals were related to populations that contributed ancestry to the Tianyuan individual in China as well as, to a lesser extent, to the GoyetQ116-1 and Ust’Ishim individuals (all |Z| < 3; Fig. 2d, Supplementary Information 6). This resolves the previously unclear relationship between the GoyetQ116-1 and Tianyuan individuals without the need for gene flow between these two geographically distant individuals. The cumulative evidence has also established that Upper Paleloithic populations in Europe and Siberia carried ‘East Asian’ lineages like Y-hg NO, C, F and mtDNA M, but these became increasingly attenuated by the Holocene.

From Hajdinjak – populations related to the IUP Bacho Kiro Cave individuals disappeared in western Eurasia without leaving a detectable genetic contribution to later populations, as indicated by the fact that later individuals, including BK1653 at Bacho Kiro Cave, were closer to present-day European populations than to present-day Asian populations.

the Bacho Kiro Cave genomes show that several distinct

modern human populations existed during the early Upper Palaeolithic

in Eurasia. Some of these populations, represented by the Oase1 and

Ust’Ishim individuals, show no detectable affinities to later popula-

tions, whereas groups related to the IUP Bacho Kiro Cave individuals

contributed to later populations with Asian ancestry as well as some

western Eurasian humans such as the GoyetQ116-1 individual in Belgium.

This is consistent with the fact that IUP archaeological assemblages are

found from central and eastern Europe to present-day Mongolia

5,15,16

(Fig.1), and a putative IUP dispersal that reached from eastern Europe

to East Asia. Eventually populations related to the IUP Bacho Kiro Cave

individuals disappeared in western Eurasia without leaving a detectable

genetic contribution to later populations, as indicated by the fact that

later individuals, including BK1653 at Bacho Kiro Cave, were closer to

present-day Europeanpopulations than to present-day Asianpopula-

tions

29,30

. In Europe, the notion of successive population replacements is

also consistent with the archaeological record, where the IUP is clearly

intrusive against the Middle Palaeolithic background and where, apart

from the common focus on blades, there are no clear technological con-

d

Evidently, IUP diversity in Europe and western Siberia diminished and was supplanted by so-called West Eurasians (with some IUP-related ancestry preserved in the western Europe and Siberia in the East)

 The earliest Bacho Kiro consists of Y-haplogroup C1, mtDNA-haplogroups U2 and U8c but the later ones are F* and F-M89. The C1 and F* are rare and found in few places in oceania nowadays. the F-M89 is found in South Asia widely and in small numbers world wide.

Vestonice: 84% Sunghir + 16% Villabruna
El Miron: 48% Villabruna + 56% Goyet
Loschbour: 91% Villabruna + 9% Goyet

Durjaya

 Durjaya was the lineage claimed by Medieval kings like Kakatiyas and Kamma caste chieftains

Durjaya occurs multiple times in Danavas who are branch of Asuras some of whom were part of Yadu tribes