Mutation in Coenzyme Q gene defines most major mtDNA haplogroups


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While analysing the mtDNA phylogeny, I noticed that most of the common, successful mitochondrial haplogroups were defined by a new mutation in the Coenzyme Q - cytochrome c reductase gene (MT-CYB) encoding the Cytochrome b protein, located between positions 14,747 and 15,887 in the mtDNA sequence.

Many macro-haplogroups are defined by such polymorphisms, including L0a'b'f, L1b, L1c, L2b’c, L3b, L3d, L3e1, L3e2, L3f, L3k, L5a, L6, M, N, HV, JT. This covers over 95% of the population of Africa and close to 100% of the people outside Africa. Many top level or major European or Middle Eastern haplogroups are also defined by additional mutations in MT-CYB, e.g. H5a1, H13, J1c, J2, J2b, T, U1, U2b’c’d’e, U3, U4, U5a, K, W, W5, X1 and X3.

The MT-CYB gene plays a critical role in biochemical generation of ATP (oxidative phosphorylation). Mutations occurring in the wrong place of the MT-CYB gene can result in exercise intolerance and multi-system pathologies.

Deleterious mutations would be so debilitating that they would be eliminated from the gene pool within a few generations. Other mutations could have no real impact (synonymous mutation), be slightly more efficient or even greatly advantageous from an evolutionary point of view. It is likely that those found in major haplogroups considerably ameliorated the functioning of the gene in certain environments. They would as a result have been positively selected, increasing the frequency of that haplogroup in the population.

Mutations that appear to have been particularly beneficial among European lineages include T14766C (haplogroup HV), A14793G (U5a), T14798C (J1c, K and T2g), C14872T (H13), G14905A (T), A15218G (U5a1), C15452a (JT), A15607G (T), G15812A (J2b), and C15833T (H5a1).

The most fascinating is T14798C, which defines three important haplogroups that were all major lineages among Neolithic farmers. It could suggest that this mutation could have become beneficial in the energy production of people with a cereal-based diet. Despite the greater variety of MT-CYB mutations among African lineages, T14798C is not found in any African mtDNA haplogroup or subclade.

Here is the list of the main haplogroups containing a mutation in the MT-CYB gene. I did not include all deep clades, but there are few of them anyway. The point of this observation is that mutations in that section of the coding region are rare and tend to result in major population explosion giving rise to a plethora of subclades of their own.

In Africa

  • L0a'b'f
  • L0b
  • L0f
  • L0d
  • L1b
  • L1c
  • L1c3
  • L2b’c (x2 mutations in MT-CYB gene)
  • L2d
  • L5a
  • L6 (x5)
  • L2'3'4'6
  • L4b1a
  • L3a1 (x2)
  • L3b (x2)
  • L3f
  • L3e1 (x2)
  • L3e2
  • L3k
  • M (x2)
  • N
  • U6a1
  • U6a2
  • U6a3
  • U6a4
  • U6a7
  • U6c

In eastern Eurasia, Oceania and America

  • B4a1a
  • B4b'd'e'j
  • B4c
  • B5a
  • B5b (x4)
  • B5b2
  • C4
  • D4a
  • D4b1
  • D4b2a
  • E2
  • G1 (x2)
  • G2a1b
  • G3a
  • M10 (x2)
  • M12
  • M15
  • M17a (x2)
  • N5a
  • N9b
  • P
  • P3
  • P4a
  • P5
  • P7
  • P9
  • U2b’c’d’e
  • U2a2
  • U2b
  • U2c
  • Z
  • Z1
  • Z2
  • Z5

In western Eurasia

  • H2a2a (CRS)
  • H5a1
  • H7d
  • H13 (+ H13a1a1a)
  • HV
  • HV1a'b'c
  • JT
  • J1c
  • J2
  • J2a2
  • J2b
  • K
  • K1b1a
  • K2a1 (x2)
  • N1a1
  • N1b2
  • R1a
  • T (x2)
  • T2g
  • T3
  • U1
  • U1b
  • U1b1
  • U2d
  • U3
  • U3c
  • U4
  • U4c
  • U5a
  • U5a1
  • U5b1a
  • U5b1c
  • U5b1i
  • U7a5
  • U9a1
  • W
  • W5
  • X1
  • X3
  • X2e
  • X2g
  • X2j
  • X2l
  • X2n

A few observations.

It is interesting to see that the most common subclades of haplogroup U, those that really prospered, are basically those that acquired a mutation in the MT-CYB gene.

Within haplogroup U2, the first mutation occurred in U2b’c’d’e. U2a2 got a mutation of its own, leaving only U2a1 without alteration in MT-CYB. The South Asian branches each got an extra mutation, unlike the European branch (U2e). This may explain why U2e remained a minor haplogroup in Europe, despite having been there for at least 33,000 years, while U2a, U2b and U2c became mainstream haplogroups in India.

Haplogroup U8 is also one of the oldest haplogroups found in ancient European remains (one 31,000-year old sample from the Czech Republic), but only one of its subclades is found in more than 0.5% of the European population. This subclade, U8b2, was renamed haplogroup K because it became over 20 times more successful than all other U8 subclades combined. It's probably not a coincidence that one of the defining mutations of haplogroup K occurred in the MT-CYB gene.

Haplogroup U6 did not develop a MT-CYB mutation like most of top level U subclades. But separate mutations occurred later in five U6a subclades (U6a1, U6a2, U6a3, U6a4, U6a7) and in U6c. Perhaps because of this diversity, U6a lineages developed a greater level of adaptation to various subclimates and thrived, while U6b remained a minor side lineage.

A MT-CYB mutation took place in macro-haplogroup JT, then again twice in haplogroup T, which became one of the most successful of all European and Middle Eastern haplogroups. After a long bottleneck evolution from JT, haplogroup T suddenly experienced a demographic explosion. MT-CYB mutations also defined J2a2 and J2b, two common subclades in the Middle East and North Africa, and J1c, the most common subclade in Europe. Rarer subclades like J1a, J2a1 and J1d didn't get any new MT-CYB mutation. J1b itself also didn't, but some of its deep subclades did (J1b1a3, J1b2a), a later development that could maybe explain why J1b was not very common in ancient European samples before the Bronze Age.

Haplogroups H and V experienced a dramatic expansion after the T14766C mutation in the MT-CYB gene and diversified quickly in over a hundred subclades. Interestingly, the subclades that quickly became the dominant ones in Neolithic Europe, namely H5a1 and H13, each got additional MT-CYB mutations. Hardly any other H subclade acquired additional MT-CYB mutations, which may be a sign that the T14766C mutation was a particularly efficient one.

Other European haplogroups outside HV, JT and UK did not generally develop MT-CYB mutations, and they remained tiny lineages like N1a, N1b, N1c, N2a, N3, R1, R2, etc. A few managed to become big enough to become new top-level haplogroups of their own. That is the case of N2b, which became haplogroup W, and N1a1b2, which became haplogroup I. Not surprisingly W is defined by a MT-CYB mutation. In haplogroup I, the MT-CYB mutation happened in N1a1, apparently major Neolithic haplogroup, but which mostly survive in the form of I today. Incidentally, haplogroup I is defined by a rare mutation in tRNA encoding Glycine, an inhibitory neurotransmitter.

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You did some deep digging, Maciamo, and you came up with some unexpected findings. Congratulations.
Maciamo, you had theorized previously that the spread of incipient farming spread with y-chromsomal lineages descended from K-M526. Although large scale farming was limited to the Near East and East Asia at the begining of the Holocene, it seems many Sapiens were doing primative gardening on some scale.

Obviously changes in the metabolism of humans can only be attributed to one of three things. 1) temperature 2) diet 3) alcohol consumption.

I would guess dietary changes is the biggest cause, especially to diets high in complex carbohydrates like Yams, Rice or Western Cereals.
Great article Maciamo and it explains a lot what we see in mt haplogroups evolution.

Maciamo, you had theorized previously that the spread of incipient farming spread with y-chromsomal lineages descended from K-M526. Although large scale farming was limited to the Near East and East Asia at the begining of the Holocene, it seems many Sapiens were doing primative gardening on some scale.
24 ky old huts excavated in Near East/ Anatolia area show multitude of grains scattered over floors. Denoting substantial amount of grains in their diet. They didn't know how to plow and seed yet but obviously they knew hot to harvest a lot of wild variety of wheat and barley.
In Near East, from 23,000 YBP to 12,000 YBP they were "Harvesters". Not farmers or herders yet, but just harvesters, a very specialized gatherers.
theorised before, based on dietary preferences of men and women, that women ate much more wheat and for much longer time than men during our evolution. Therefore it was logical to conclude that women did gardening/harvesting for twice longer than men. Women harvested/gathered wheats for over 20 ky, men farms for bit over 10ky, in some areas of Europe for less than 5 ky.
The Harvesters invented first sickle and flat bread, and developed many needed farmer mutations, to give beginning to full scale farming.

I would assume movement of these harvester societies (perhaps Y hg E1b1b) into Balkans because of similarity of the climate and close location..
It's interesting that neither H1 or H3 appear here.

And we have to take into account that both lineages became predominant in the Neolithic and remained the most common since.

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