Thoughts About 16519??

[GregKiroKH2]

Some markers have high mutation rates while others are seen in very old lineages. T16086C ( http://www.isogg.org/ for HVR-1 AF254446) is seen in Neanderthal mtDNA as is C16223T. Markers like 16519 can be used to ID sub-clades. I was looking for the frequencies of 16519 mutations in Native African populations at one time, and I never found it.

Nucleotides 263A, 311C-315C, 750A, 1438A, 4769A, 8860A, and 15326A are considered to be rare polymorphisms and are maintained as part of the true reference sequence.
http://www.mitomap.org/mitoseq.html

GregKiroKH2:

the hotspots (16519, 309.1 and 315.1, deletions around 522) are not related to each other, they can happen in any combination in any haplogroup.

And I had never heard of 16223 as a neanderthal marker. 16233 is the ancestral state. It is in the Western Eurasian lineages that 16233 mutated.

Neanderthals must have separated from modern humans around 400-500K years ago, which in evolutionary terms is a small time. The vast majority of their mtdna is the same as that of modern humans.

Btw, interesting quote about African American mtdna. The few A,B,C and some of the M are Native American, not Western Eurasian. Some African Americans married Native Americans.

cacio

[cacio]

GregKiroKH2:

I am not aware of any site for the particular purpose of checking the frequency of 16519, however, a starting point could be:

http://www.genpat.uu.se/mtDB/

click on Search for specific variants, then insert 16519 C (or whatever other value you are interested in). It will give you a list of sequences containing it. It doesn't tell the haplogroup, but it tells you where the sequences come from.

The frequency from mitosearch.org can instead be found here:

http://freepages.genealogy.rootsweb.com/~ncscotts/mtDNA/mtDNA%20HVR1%20Mutation%20Distribution.htm

The frequency of 16519 in L sequences is 282/455.

cacio

[GregKiroKH2]

I am just kicking around some ideas between indigenous people and those who have recent or non-ancestral homelands. Why does a variant occur? My notion is that some mutations occur in clusters while others are individual.

While mtDNA evidence has significant potential as a law enforcement tool, the SWGDAM database is currently too small and insufficiently representative to provide meaningful estimates of sequence frequencies. Most importantly, the database fails to account for historic and recent human migration patterns that, because mtDNA is maternally inherited and not recombinant, have resulted in significant regional differences in sequence frequencies.
http://www.bioforensics.com/articles...imitations.pdf

I think the database is too small too to do the historical research I would like to do. However, it is still interesting. Without an historical database it is elementary challenging to find the various pathways of similar markers such as 16519.

GregKiroKH2:

I am not aware of any site for the particular purpose of checking the frequency of 16519, however, a starting point could be:

http://www.genpat.uu.se/mtDB/

click on Search for specific variants, then insert 16519 C (or whatever other value you are interested in). It will give you a list of sequences containing it. It doesn't tell the haplogroup, but it tells you where the sequences come from.

The frequency from mitosearch.org can instead be found here:

http://freepages.genealogy.rootsweb.com/~ncscotts/mtDNA/mtDNA%20HVR1%20Mutation%20Distribution.htm

The frequency of 16519 in L sequences is 282/455.

cacio

In the case of the nt 10793 variant the two reports occur in independent ... The tumor-specific somatic mutations at nt 73, 16189, 16311 and 16519 (Yoneyama ...

http://www.nature.com/onc/journal/v25/n34/full/1209607a.html

Heteroplasmic and homoplasmic sequence variants occur in the mitochondrial ... nucleotide position 16519 (within the D-loop) that was not confirmed at NIST. ...
Two of the sequence variants identified (22%) were found in the D-loop region, which accounts for 6.8% of the mitochondrial genome.

http://jmd.amjpathol.org/cgi/content/full/7/2/258

[vineviz]

I am just kicking around some ideas between indigenous people and those who have recent or non-ancestral homelands. Why does a variant occur? My notion is that some mutations occur in clusters while others are individual.

The evidence is pretty compelling that mutations in mtDNA occur independently, especially in the control region.

And 16519 is particularly uninformative marker, given its high rate of mutation.

Depending on the focus of a phylogenetic analysis, one might even wish to disregard (i.e. give weight 0 to) the ten extreme hotspot transitions at positions 146, 150, 152, 195, 16093, 16129, 16189, 16311, 16362, and 16519.

[GregKiroKH2]

I understand those points of investigation. I was just wondering how the variants changed in pathway two of my mtDNA
Path two:
L0 to H2
L0 to L3 G769A T825A G1018A G2758A T2885C C3594T A4104G A7146G C7256T G7521A C8468T C8655T G10688A T10810C A13105G C13506T C13650T G15301A
L3 to N A8701G T9540C A10398G T10873C (G15301A)
N to R C12705T
R to preH G11719A
preH to HV C14766T
HV to H A2706G C7028T
H to H2 A1438G A4769G

Maybe, it is just an idiosyncrasy of how our naming system has been set up. However, on my vacation after two days of just looking at data, I was surprise to see how the puzzle came together in clusters and not individual markers, defiantly not individual markers.

The evidence is pretty compelling that mutations in mtDNA occur independently, especially in the control region.

And 16519 is particularly uninformative marker, given its high rate of mutation.

16519 seemed to have a mind of its own thou . . .

[vineviz]

Maybe, it is just an idiosyncrasy of how our naming system has been set up. However, on my vacation after two days of just looking at data, I was surprise to see how the puzzle came together in clusters and not individual markers, defiantly not individual markers.

There is no doubt that markers mutate individually. Each of those markers that separate L0 from H2 occurred individually. In many cases multiple mutations occurred between the founding of one haplogroup and the founding of a downstream clade, but that doesn't change the nature of the genomics.

16519 seemed to have a mind of its own thou . . .

I'm not sure what you mean by that. 16519 is one of the hottest of the hot positions, and is not generally very useful phylogenetically except at the very tips of the tree.

[GregKiroKH2]

Do you mean the time independent or time dependent case? Let us just assume that most people do not understand differential equations, and we assume the time dependent case within a generation.

In the first place, I have no idea why the polymorphism 16519 mutates faster than say 16223. And I would like to know because 16519 might have a branch in every haplogroup (which is amazing to me)! Why are the mutations in Africa different than the mutations in Asia or Europe? Some articles mention diet and climate. Maybe, it does not matter where the person is for a 16519 mutation. What really makes me ponder is the frequency of the people who only have one polymorphism for any haplogroup which require multiple polymorphisms and still belong to that haplogroup. From my understanding, one polymorphism does not normally make up a haplogroup. Suppose we have a hypothetical haplogroup which requires two polymorphisms and allows recent mutations. Since all haplogroups are derived from an ancestral haplogroup, mutations will occur as they occur. So, we ask, how do they occur? Just by statistics alone, if each mutation occurred independently and randomly, then there would be an equal number of people in one of two population groups. One population would have one of two haplogroup polymorphisms and another population would have the other of two haplogroup polymorphisms. This would be seen in many haplogroups. What then does it mean when almost all of the population has all of polymorphisms for our hypothetical haplogroup, and almost no one having a partial polymorphism in haplogroup after haplogroup? I have seen overlapping polymorphisms from older haplogroups into newer ones but this just means than some mutations did not happened.
I would like to read the research articles on the subject because I am making an observation based on my full mtDNA. And if anyone has done population frequency studies on how each allele mutates and changes into a polymorphism in mtDNA, then I would find that interesting. Codons are groups of three alleles which code for an amino acid. There are many things in genetics which require a set of genes. Still, I have no idea of studies involving full mtDNA mutations and population frequencies which will tell me why a mutation will occur and at what rate. So as for now, I have no idea why a hot spot mutates quickly while cold spots do not. Quick mutations might suggest an adaptive mechanism for physiological defense or something like that.

There is no doubt that markers mutate individually. Each of those markers that separate L0 from H2 occurred individually. In many cases multiple mutations occurred between the founding of one haplogroup and the founding of a downstream clade, but that doesn't change the nature of the genomics.



I'm not sure what you mean by that. 16519 is one of the hottest of the hot positions, and is not generally very useful phylogenetically except at the very tips of the tree.

[vineviz]

In the first place, I have no idea why the polymorphism 16519 mutates faster than say 16223.

I'm not sure anyone really has a good idea and, unless you aspire to be a geneticist I'm not sure it is a very interesting question.

And I would like to know because 16519 might have a branch in every haplogroup (which is amazing to me)!

Mutations at 16519 do appear in many haplogroups (a result of being a hotspot), which is precisely what makes it relatively uninformative phylogenetically.

Why are the mutations in Africa different than the mutations in Asia or Europe?

Who says they are?

What really makes me ponder is the frequency of the people who only have one polymorphism for any haplogroup which require multiple polymorphisms and still belong to that haplogroup.

Broadly speaking, this cannot be true by definition. If you lack the haplotype that defines a haplogroup, you do not belong to it.

From my understanding, one polymorphism does not normally make up a haplogroup.

Some haplogroups are defined by a single polymorphism, and others by multiple polymorphisms. It just depends on how things shake out in that particular part of the tree.

Suppose we have a hypothetical haplogroup which requires two polymorphisms . . . but this just means than some mutations did not happened.

This part made no sense to me. I can say that there are lots of reasons that haplogroups vary in size and frequency.

Quick mutations might suggest an adaptive mechanism for physiological defense or something like that.

In the HVR region, this is almost certainly not the case since little or no biological function is associated with the control region.

[GregKiroKH2]

I am not sure. After all, I am kicking around some ideas . . . I wrote some informal papers on type one and type two muscles. The idea of having to escape wild animals like the saber tooth tiger or adapting to new climate conditions have fascinated me in the past. Muscle and brain development is very important to the mtDNA. So, environmental conditions dictate survival. If one does not have the needed survival skills, then the individual will not reproduce, right or wrong has nothing to do with it. Mitomap has a good write up on adaptive ancient mtDNA. Also, the Ruiz-Pesini et al. 2004:226 article mentions it too. The research in the literature might suggest that some alleles are more adaptive in humans than other alleles in humans. So, how is human mtDNA different from plant mtDNA and such?

It is now clear that two major discontinuities exist in mtDNA variation: between tropical and sub-tropical Africa and temperate Eurasia and between temperate Eurasia and the arctic. Moreover, these discontinuities are the product of the appearance of new functional mtDNA mutations that shifted the OXPHOS energy output from predominately ATP production and very little heat production in tropical Africa to subsequently increased heat production at the expense of ATP production in the temperate and arctic zones. About 25% of all ancient mtDNA sequence variation appears to have been adaptive [10][11]. This same variation is now being discovered by multiple investigators to influence longevity, predisposition to age-related degenerative diseases such as AD and PD, and to influence the clinical expression of the milder nDNA and mtDNA pathogenic gene mutations [1].
Amazingly, many of these same ancient human adaptive mtDNA mutations have also been found to arise as new somatic mutations as cells undergo neoplastic transformation to become malignant cancer cells. This makes a kind of sense since the cancer cell must adapt to new environmental conditions as have humans. In both cases the environmental conditions affect the availability of energy substrates, oxygen tension, and ROS toxicity, all the purview of the mitochondria [8].
http://mitomap.bio.uci.edu/mammag/Premise.html

. . .

Who says they are?


. . .

This hypothesis is supported by the fact that missense mutations in mtDNA protein genes show regional specificity. Missense mutations are prevalent in the ATP6 gene in the arctic, in the cytb gene in Europe, and in the COI gene in Africa. Mutations in different ND genes also show regional correlation (Mishmar et al., 2003). . . .

The relative frequency and amino acid conservation of internal branch replacement mutations was found to increase from tropical Africa to temperate Europe and arctic northeastern Siberia. Particularly highly conserved amino acid substitutions were found at the roots of multiple mtDNA lineages from higher latitudes. These same lineages correlate with increased propensity for energy deficiency diseases as well as longevity. Thus, specific mtDNA replacement mutations permitted our ancestors to adapt to more northern climates, and these same variants are influencing our health today.

http://www.johnhawks.net/weblog/reviews/neandertals/neandertal_dna/ruiz-pesini_selection_mtdna_2004.w

This combination of the increased predilection to energy deficiency diseases, but protection from neurodegenerative diseases and aging is consistent with the expectations for mtDNA coupling efficiency mutations. Uncoupling mutations would reduce ATP production, increasing the probability of energetic failure. However, they would also decrease mitochondrial ROS production by increasing the oxidation of the electron transport chain, thus reducing oxidative damage and apoptosis. This could decrease neuronal and other cell loss, thus increasing longevity.
Our observations support the hypothesis that certain ancient mtDNA variants permitted humans to adapt to colder climates, resulting in the regional enrichment of specific mtDNA lineages (haplogroups). Today these same variants result in differences in energy metabolism and altered mitochondrial oxidative damage, thus affecting health and longevity. Therefore, to understand individual predisposition to modern diseases, we must also understand our genetic past, the goal of the new discipline of evolutionary medicine (Ruiz-Pesini et al. 2004:226).

Galtier and his colleagues suggest the pattern of diversity in mitochondria could be explained by natural selection. Some beneficial mutations can mute variation in linked loci, a process called "hitchhiking" that mtDNA is especially prone to because of its relative lack of recombination. The larger a population gets, the more opportunities there are to accumulate adaptive mtDNA mutations. More adaptive mutations could freeze more hitched loci, the authors reasoned, perhaps explaining why mtDNA diversity remained similar across taxa, regardless of population size.

Indeed, the authors found that 58% of amino acid substitutions appear adaptive in invertebrate mtDNA, compared to 12% in vertebrates, supporting their notion that the rate of adaptive evolution is proportional to population size. Natural selection pressures mitochondria could experience might include "the genomic conflict between mitochondrial and nuclear DNA," Galtier noted.
. . .
David Rand of Brown University in Rhode Island, also not a co-author, described the paper as "a strong indictment of the use of mtDNA as a neutral marker." Still, he said he was concerned that the new study ignored rare polymorphisms, which would bias results toward positive selection. "It would be useful to repeat the analyses with all polymorphisms included to see if the difference between invertebrates and vertebrates is upheld."
Interestingly, humans do not display the same pattern Galtier and his colleagues found, Eyre-Walker noted -- suggesting humans may have such a small population that adaptive evolution in the mitochondrial genome is very rare.
http://www.the-scientist.com/news/display/23350/

. . . and as it relates to nuclear-mitochondrial communication problems.
http://chroma.med.miami.edu/cellbio/...ty_moraes.html

[vineviz]

I'm still not sure it is fair to say that "mutations in Africa are different", since that implies that the mechanism is different but now I think see what you were thinking about.

It is not hard to imagine that there may be some selection in the coding region of mtDNA, and that such selection might be visible in regional differences between people. But that would not really be relevant to the HVR region, including 16519.

[mari]

Thanks for the links Greg

I find this stuff Very interesting ..
And there are a lot of us who have more than one "hot spot" and it makes sence that there is a reason and not just a region for the mutations. But what happened to make them, and when, now I am really interested.
mari

[GregKiroKH2]

We are still looking for the reasons why alleles mutate. If we knew the answer, then we could cure many diseases. I found this in a basic biology link:

In 1966, studies by Lewontin and Hubby and by Harris provided the first more-or-less direct estimates of genetic variation at individual loci. They showed that protein electrophoresis could be used to survey levels of allozyme variation among individuals within a population or species.
…
Despite its crucial importance, we can think of mutation as a necessary but not sufficient force in driving microevolutionary (allele frequency) change in populations. There are several reasons for this. First, mutation rates are typically low, especially for protein-coding loci; forward mutation rates generally range from 10-6 for visible mutations to perhaps 10-2 for highly variable VNTR loci. Backward mutation rates are generally at least an order of magnitude lower, but decrease the net accumulation of mutants; in fact, every locus has a point of mutational equilibrium at which the net effect of forward and backward mutations is equivalent, and allele frequencies will remain constant.
http://bioweb.wku.edu/courses/Biol430/430lects5.htm

The first time I saw an attempt to address differences in African and European and Asian genes was in my Ecology book. And the teacher, Dr. Fan, thought it needed more work. He thought talking about ecotones would be more interesting.

I'm still not sure it is fair to say that "mutations in Africa are different", since that implies that the mechanism is different but now I think see what you were thinking about.

It is not hard to imagine that there may be some selection in the coding region of mtDNA, and that such selection might be visible in regional differences between people. But that would not really be relevant to the HVR region, including 16519.

Thanks, Mari . . . I find it interesting too . . .

I find this stuff Very interesting ..
And there are a lot of us who have more than one "hot spot" and it makes sence that there is a reason and not just a region for the mutations. But what happened to make them, and when, now I am really interested.
mari

[Bill Hurst]

There is no doubt that markers mutate individually. Each of those markers that separate L0 from H2 occurred individually. In many cases multiple mutations occurred between the founding of one haplogroup and the founding of a downstream clade, but that doesn't change the nature of the genomics.

....16519 is one of the hottest of the hot positions, and is not generally very useful phylogenetically except at the very tips of the tree.

First of all, I've never like to hear 16519C called a "hotspot." The original K, for example, had 16519C, I believe, and virtually every K since has had it. A couple of members of the K Project have had a back mutation there, but so far I've never seen a cluster formed from those without it. To me, hotspots would be heteroplasmic mutations like 16093C or 309.1C where we see siblings differing.

Also, I'm not sure about the comment "markers mutate individually." As an example, my K1c2 requires three coding-region mutations plus 16320T. So either those four happened at the same time, or about the same, or any haplotypes with only, say, two of those together didn't survive. 16320T does show up in other subclades, but not, to my knowledge, the coding-region mutations.

There are several mechanisms which cause perceived mtDNA mutations. One a SNP or single nucleotide polymorphism; for exampe, a C changes to a T. Two, heteroplasmy, which means that a person may have two or more variants, 16093T (which is not reported since it is the CRS variant) or 16093C. The actual mutation may have occurred tens of thousands of years ago, with many lines carrying both variants, which occasionally swap the position of dominance. So in the recently reported example with siblings having different values for that position, no piece of DNA had a change from T to C; instead, the C variant just became dominant, by random chance, in that person. You might find lines or subclades where the variants are about 50-50, so the dominant one will change fairly often. In other subclades or lines, one variant may disappear entirely and the other one becomes "fixed." I've found two subclades within K where there are no known examples of 309.1C, which otherwise is very common in K and mtDNA in general. That mutation is actually example of a third type of "mutation" in mtDNA, "length heteroplasmy," where the copying mechanism loses track of the number C's in a poly-C tract. This "replication slippage" is similar to Y-DNA STRs. Again, the actual slippage may have taken place thousands of years ago, with each individual having both variants and possibly the less common third one, 309.2C. Length heteroplasmy also applies to the CA pairs added at position 524. Ha, another example of mutations always occurring together! The individuals in many K subclades probably have three variants of the 524 position. The K1b2 subclade has four, from zero to three pairs.

There are probably cases where it would be difficult to determine whether a mutation was caused by a nucletide change or by heteroplasmy.

By the way, Greg, in K 16223T is more variable than 16519C.

Ain't mtDNA fun?

Bill Hurst

[GregKiroKH2]

What does hot spot mean? Is it a place people talk about? And is a cold spot a place people ignore?

Length heteroplasmy - The presence of mtDNA molecules that differ in length.

Variant - A dissimilarity in the commonly occuring sequence of a gene.

Polymorphism - Variations in DNA sequences in a population that are detected in human DNA identification testing.

Marker - Pieces of DNA sequence of known locations on chromosomes that are used to identify the specific genetic variations an individual possesses.

Mutation – Recent change in DNA sequence which could become a polymorphism

I had a big mental ping pong match over length heteroplasmy when I first read my mtDNA results. I counted a base count of 16566 compared to the rCRS base count of 16568. So, it was hard to align them up with the base count of 16569. Rather, I should think why 522delC 523delA 2395delA are really insertions. 522delC and 523del A are D loop while 2395delA is related to the highly conserved 16s rRNA. Using a dummy marker like they did in the rCRS helped me. However, genetic patterns are recognized in real life without the dummy markers.

There is also evidence that 16S rRNA is directly involved in the interactions between the large and small ribosomal subunits.

The sequence of 16S rRNA is highly conserved among all organisms due to the antiquity of the protein-synthesizing process. Thus ribosomal RNA is an excellent molecule for discerning evolutionary relationships among prokaryotic organismsms. Ribosomal RNAs are ancient molecules, functionally constant, universally distributed, and moderately well conserved across broad phylogenetic distances. Various regions within the rRNA genes evolve at slightly different rates due to the fact that 16S rRNA is functionally involved in the protein biosynthesis process and involved in different interactions in the ribosome. This results in alternating regions in the rRNA sequences of nucleotide conservation and variability.

The 16S rRNA of most major phylogenetic groups has one or more characteristic nucleotide sequences called oligonucleotide signatures. Oligonucleotide signature sequences are specific sequences that occur in most or all members of a particular phylogenetic group. Because the number of different possible sequences is so large, similarity in two sequences always indicate some phylogenetic relationship. However, it is the degree of similarity in the sequences between two organisms that indicates their relative evolutionary relatedness. Thus signature sequences can be used to place microorganisms in the proper group.
http://prion.bchs.uh.edu/Signature16S/Molecule.html

The D-loop seems to be associated with the control region. So, this must be true for 16519 too. I like to think of it as communication.

[vineviz]

What does hot spot mean? Is it a place people talk about? And is a cold spot a place people ignore?

A hot spot is a marker that is prone to frequent (or recurrent) mutations.