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Mutations in Coenzyme Q gene define most major mtDNA haplogroups

Author: Maciamo Hay

Positive selection for beneficial polymorphisms in the MT-CYB gene appear to have played a major role in mitochondrial evolution in human populations.

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, L2bc, L3b, L3d, L3e1, L3e2, L3f, L3k, L5a, L6, M, N, HV, JT, which effectively cover 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. in haplogroups H5a1, H13, J1c, J2, J2b, T, U1, U2bcde, 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 (defining haplogroup HV), A14793G (U5a), T14798C (J1c, K and T2g), C14872T (H13), G14905A (T), A15218G (U5a1), C15452a (JT), A15607G (T), G15812A (J2b), and C15833T (H5a1).


Cytochrome bc1 complex (Creative Commons Attribution-Share Alike 3.0 Unported license. Attribution: C31004 at en.wikipedia)
Cytochrome bc1 complex

The most fascinating is T14798C defining J1c, K and T2g, three major lineages among Neolithic farmers. Coincidences of that magnitude don't normally happen in nature. It rather suggest that this mutation would have become beneficial in the energy production of people with a cereal-based diet, and would consequently have been positively selected among early farmers. Despite the greater variety of MT-CYB mutations among African lineages, T14798C is not found in any African mtDNA haplogroup or subclade, which reinforces the hypothesis that T14798C was mostly beneficial for cereal farmers rather than hunters or stock breeders.

Here is the list of the main haplogroups containing a mutation in the MT-CYB gene. Only the most common deep clades are listed to avoid cluttering the data. The purpose of this analysis is to show that evolutionary advantageous mutations in the Coenzyme Q gene are rare, but when they do occur they usually results in major expansions of the affected mitochondiral lineages, as attested by the high frequency of the newly founded haplogroups and the plethora of subclades downstream of the new mutation.

In Africa

  • L0a'b'f
  • L0b
  • L0f
  • L0d
  • L1b
  • L1c
  • L1c3
  • L2bc (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
  • U2bcde
  • 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


Haplogroup U

Mutations in the Coenzyme Q gene define almost all of haplogroup U's top-level subclades (U1, U3, U4) or near top-level subclades (U2bcde , U2a2, U5a, U5b1, U6a1, U6a2, U6a3, U6a4, U6a7, U6c, U7a5 and U9a1). In fact, subclades that did not develop new mutations in the MT-CYB gene did not prosper and have become exceedingly rare nowadays. The only notable exception is U5b2.

Within haplogroup U2, the first mutation occurred in U2bcde. U2a2 got a mutation of its own, leaving only U2a1 without alteration in MT-CYB. The two main South Asian branches (U2b and U2c) each got an extra mutation, unlike the European branch (U2e). This may explain why U2e remained a minor haplogroup in Europe (about 1% of the population), despite having been there for at least 33,000 years, while U2a, U2b and U2c all became mainstream haplogroups in India and Pakistan, making up approximately 15% of the population together.

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.

Haplogroups HV and JT

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

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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