ABCC11

from Wikipedia, the free encyclopedia
ATP binding cassette, subfamily C (CFTR / MRP),
member 11
Properties of human protein
Mass / length primary structure 1382 amino acids (isoform: 1344 aa)
Cofactor ATP
Identifier
Gene names ABCC11 MRP8
External IDs
Enzyme classification
Substrate lipophilic anions
Orthologue (human)
Entrez 85320
Ensemble ENSG00000121270
UniProt Q96J66
Refseq (mRNA) NM_032583
Refseq (protein) NP_115972
Gene locus Chr 16: 48.17 - 48.25 Mb
PubMed search 85320

The protein ABCC11 ( ATP-binding cassette sub-family C member 11 , dt . : 'ATP-binding cassette , subfamily C (CFTR / MRP), member 11'), also MRP8 ( Multidrug Resistance-Related Protein 8 , dt .: 'Resistance to multiple drugs, protein 8') is a membrane transporter that transports certain molecules from inside a cell . ABCC11 is mainly found in apocrine glands , i.e. scent glands that end in hair follicles , for example . The corresponding ABCC11 gene has so far only been found in a few mammalian species , including humans. In humans, it is on chromosome 16 . A large number of people, especially in Northeast Asia, do not have a functioning ABCC11. The reason for this is a point mutation in the ABCC11 gene. The two genotypes lead to visibly different characteristics ( phenotypic variation ). For example, people in whom both ABCC11 genes have the mutation on the corresponding chromosome pair have white, dry ear wax and only a faint body odor . The wild type with two “normal” ABCC11 genes and the heterozygous type with a defective ABCC11 gene, on the other hand, have yellowish, moist ear wax and a more pronounced body odor. The genetic defect is inherited recessively . The regional frequency of the point mutation provides important clues about the spread of humans across the earth and the mixing of different populations .

genetics

The location of ABCC11 with its 30 exons on chromosome 16. Exon 4 contains the important single nucleotide polymorphism (SNP) 539G → A.

In humans, the ABCC11 gene is located on chromosome 16 , gene locus q12.1. The genomic coordinates (according to GRCh37) are 16: 48.200.781-48.281.478. The gene thus consists of 80,697 base pairs (bp). These are divided into 30 exons .

In 2001 ABCC11 was isolated for the first time from the cDNA library of a human liver by three working groups independently of one another . In the immediate vicinity, on the same gene locus and only about 20 kbp apart, lies the ABCC12 gene - in tail-to-head orientation to ABCC11 . Both genes are very similar to one another and to ABCC3 and ABCC5 . They also have two ATP- binding cassettes and twelve transmembrane helices .

The ABCC11 gene has so far only been found in mammals. Through cloning , it has so far for the following types of evidence are (as of September 2014): Human ( Homo sapiens ), Common Chimpanzee ( Pan troglodytes ), Western Lowland Gorilla ( Gorilla gorilla gorilla ), Sumatran orangutan ( Pongo abelii ), Northern Barnacle -Schopfgibbon ( Nomascus leucogenys ), rhesus monkey ( Macaca mulatta ), common marmoset ( Callithrix jacchus ), Philippines Koboldmaki ( tarsius syrichta ), Northern Greater Galago ( Otolemur Garnettii ), rabbit ( Oryctolagus cuniculus ), northern treeshrew ( Tupaia belangeri ), African Elephant ( Loxodonta africana ), small hedgehog ( Echinops telfairi ), domestic dog ( Canis familiaris ), ferret ( Mustela putorius furo ), giant panda ( Ailuropoda melanoleuca ), domestic cat ( Felis catus ), bottlenose dolphin ( Tursiops truncatus ), domestic cattle ( Bos taurus ) Sheep , domestic sheep ( Ovis aries ), alpaca ( Vicugna pacos ), brown-breasted hedgehog ( Erinaceus europaeus ), wood shrew ( Sorex araneus ), domestic horse ( Equus caballus ), Tasmanian devils ( Sarcophilus harrisii ), platypus ( Ornithorhynchus anatinus ) and tammar wallaby ( Macropus eugenii ).

In the model organisms rat and mouse, there is no gene corresponding to human ABCC11 ( orthologous gene ). ABCC11 is a paralogous gene that arose from ABCC12 through gene duplication in the course of evolution . The corresponding orthologous genes are found in rodents and many other animals for human ABCC12 .

By means of transcriptional analysis it was found that the ABCC11 mRNA is expressed in all adult and fetal tissues . Particularly large amounts of ABCC11 mRNA are found in breast cancer tissue.

Proteomics

The ABCC11 gene codes for a protein consisting of 1382 amino acids , the sequence of which is approximately 47% identical to MRP9, the gene product of ABCC12 . A splice variant of ABCC11 (variant A) leads to a gene product with 1344 amino acids. The reason for this is the complete loss of exon 28. Variant A also has twelve transmembrane helices, but the second ATP-binding cassette is missing 38 amino acids in positions 1261 to 1298. This variant is expressed by the cells to about 25%.

function

Apocrine sweat glands (scent glands) are only found in areas of hairy skin and belong to the hair-sebum gland unit.
Schematic structure of the ABCC11 protein. The extracellular space is located above the cell membrane (blue) . The rectangles (gray) represent the twelve transmembrane helices. The long loops in the intracellular space symbolize the two ATP-binding cassettes (ATP in green). The areas marked N838 and N844 are two asparagines that are glycosylated (red). The areas of single nucleotide polymorphisms currently known (as of 2013) are marked on the protein. Δ27 is a 27 base pair deletion in exon 29.
Structure of ABCC11 calculated on the basis of the sequence of ABCC11 and with data from the murine ABC transporters ABCB1 and Sav1866.
On the left, the inward-facing conformation for taking up a substrate from the intracellular space. On the right the conformation directed into the extracellular space for the release of the substrate. EZS = extracellular loop, TS = transmembrane segment, MSD = membrane-spanning domain, IZS = intracellular loop, ABC = ATP-binding cassette. The hinge is the fulcrum that gives the protein its flexibility to change its conformation. There are no data yet for the crystal structure of the ABCC11 protein, as crystallization has not yet been successful (as of September 2014).

ABCC11 is a membrane transporter (outdated: efflux pump ). These are membrane-based transport proteins that carry certain molecules ( substrates ) specific for the transporter out of the cell or a cell compartment . ABCC11 belongs to the family of ABC transporters (ABC = ATP binding cassette ). These membrane proteins have at least one ATP-binding cassette (ATP = adenosine triphosphate ) as a common structural element . If the concentration of a substrate outside the cell is higher than inside, then energy must be expended for the transport process against this concentration gradient . In the case of the ABC transporter, this happens through the binding and hydrolysis of the cellular energy carrier ATP, in the ATP-binding cassette.

The human genome comprises 48 ABC transporters, which are divided into three subfamilies (ABCA, ABCB and ABCC). The ABCC subfamily has ten members, the Multidrug Resistance-Related Proteins (MRP). An important ABCC transporter, for example, is the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), the key protein in the hereditary disease cystic fibrosis . Substrates for ABCC11 are lipophilic anions . These include cyclic nucleotide monophosphates (cNMP) such as cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), glutathione - conjugates such as leukotriene C4 and 2,4-dinitrophenyl S -Glutathion (DNP-SG), steroid - Sulfate such as estrone -3-sulfate (E13S) and dehydroepiandrosterone -3-sulfate (DHEAS), glucuronides such as estradiol -17-β- D - glucuronide , the bile acids glyco- and taurocholic acid and folic acid . The related transporters ABCC4 and ABCC5 show a high structural similarity to ABCC11. As a result, all three have very similar target substrates.

The abcc11 protein is mainly in the epithelial cells of the apocrine sweat glands ( glands sudoriferae apocrinae ) expressed . The apocrine sweat glands, also known as 'scent glands', are found in areas of hairy skin in humans, especially in the armpits, in the genital and anal areas, the nipples and the areola and the nasal vestibule . A scent gland is a tube-like (tubular) ball. Inside the tubule there are epithelial cells in a single layer. From these cells, cytoplasmic domes protrude into the tubule. These tips are pinched off during secretion and released into the interior of the tubule (the lumen). The epithelial cells lose part of their cytoplasm and their cell membrane. This apocrine secretion is also called apocytosis . Modified apocrine sweat glands are located on the edge of the eyelashes, the minor glands ( glandulae ciliares conjunctivales ), and in the external auditory canals, the ear wax glands ( glandulae ceruminosae ).

In addition to the epithelium of the apocrine sweat glands, ABCC11 is also expressed on liver cells , white blood cells and blasts in the bone marrow .

The expression of ABCC11 is regulated via the estrogen receptor -α. Expression is reduced by estradiol . Correspondingly, the expression is upregulated by tamoxifen , an estradiol antagonist which binds to the estrogen receptor-α via competitive inhibition .

Multidrug Resistance

Cyclic adenosine monophosphate (cAMP), a natural substrate for ABCC11
Adefovir, an exogenous substrate for ABCC11

Cancer cells have a high rate of mutation and cell division . They are constantly on survival and proliferation selected . During this evolutionary process, the degenerate cells use basic physiological mechanisms to protect themselves from the toxic effects of chemotherapy . One of these mechanisms is the transport (efflux) of chemotherapeutic agents out of the cell. A large number of studies have shown that the efflux increases over the duration of treatment, i.e. over the number of therapy cycles, with a chemotherapeutic agent. The cancer cells express more and more transporters in order to be able to "pump out" substances that are toxic for the cell. For the treated patient, this means that his tumor or its metastases no longer respond to the active substance because a drug resistance has developed. As a rule - if available - a structurally different chemotherapeutic agent is used, which ideally is not a suitable substrate for the overexpressed transporters. In principle, the development of resistance in cancer cells, but also in cells infected with viruses, is extremely unfavorable for the success of the therapy.

The ABC transporters, to which ABCC11 also belongs, are responsible for the transport of active substances out of the cell. Hence the name Multidrug Resistance-Related Protein 8 for ABCC11. These drugs that can transport ABCC11 out of the cell include nucleoside and folic acid analogues. Nucleoside analogues are for example the important chemotherapeutic agent 5-fluorouracil (5-FU) and its derivatives floxuridine and doxifluridine , and cytarabine , the HIV -Therapeutikum zalcitabine and the hepatitis B drug adefovir . Cells that overexpress ABCC11 can survive an approximately three-fold higher dose of 5-FU and doxifluridine compared to normal cells, 5-fold in the case of floxuridine and adefovir, and 6-fold the dose for zalcitabine. The folic acid analog methotrexate (MTX) is also a substrate for ABCC11. The administration of 5-fluorouracil directly affects the expression of ABCC11.

Genetic Polymorphism

Transcription and translation of the ABCC11 gene in the wild type. The amino acid glycine is translated from the base triplet GGG .
Transcription and translation of the ABCC11 gene in SNP 538G → A. The amino acid arginine is translated from the base triplet AGG .

So far (as of 2013) are more than ten non-synonymous single nucleotide polymorphisms (Engl. Polymorphism single nucleotide , SNP) in human abcc11 known gene. Non-synonymous SNPs are variations of single base pairs in a gene that lead to a single amino acid being exchanged in the gene product - the protein. Non-synonymous SNPs are a special form of a point mutation that occurs frequently in at least 1% of the respective population and has successfully established itself in the gene pool of this population. Polymorphism is the term used to describe the occurrence of several gene variants within a population.

The single nucleotide polymorphism rs17822931
Section from the nucleotide or amino acid sequence of ABCC11
Wild type
(base sequence of the sense strand) 		         ▾530       ▾538           ▾550       
ATT GCC AGT GTA CTC GGG CCA ATA TTG ATT ATA CCA
Wild type
(amino acid sequence) 		175 176 177 178 179 180 181 182 183 184 185 186
Ile Ala Ser Val Leu Gly Pro Ile Leu Ile Ile Pro
538G → A / Gly180Arg
(base sequence of the sense strand) 		         ▾530       ▾538           ▾550       
ATT GCC AGT GTA CTC AGG CCA ATA TTG ATT ATA CCA
538G → A / Gly180Arg
(amino acid sequence) 		175 176 177 178 179 180 181 182 183 184 185 186
Ile Ala Ser Val Leu Arg Pro Ile Leu Ile Ile Pro

The SNP rs17822931 is of particular importance. In this mutation, the nucleobase guanine (G) in position 538 is replaced by adenine (538G → A). The original base triplet GGG becomes AGG . While GGG codes for the amino acid glycine , AGG codes for arginine . Therefore, in protein biosynthesis in the ABCC11 protein after translation , arginine is incorporated in position 180 instead of glycine (Gly180Arg). This amino acid exchange has the effect that a correct post-translational N -glycolization of asparagine in positions 838 and 844 of the protein in the endoplasmic reticulum is not possible. This in turn causes the protein to fold 'incorrectly' . This misfolding is recognized by the protein quality control, the faulty ABCC11 is ubiquitinylated , i.e. marked as faulty, and then broken down in the proteasome . The single nucleotide polymorphism 538G → A consequently leads to a loss of function in the affected gene. The protein secreted by the protein quality control is not expressed on the cell membrane. In such cases, one speaks of a loss-of-function mutation . Like most loss-of-function mutations, the 538G → A mutation is inherited recessively .

The phenotypes of the single nucleotide polymorphism 538G → A known to date are shown below. The other non-synonymous single nucleotide polymorphisms are much rarer and comparatively meaningless. In addition to the single nucleotide polymorphisms, a deletion of 27 base pairs in exon 29 is also described in the literature. This mutation, designated Δ27 or 3939-3965del27, is comparatively rare. In a 2007 screening of 722 subjects in seven Japanese and one Korean and German populations, only two subjects, one from Yamagata Prefecture and one from Korea, had this mutation. A test person in whom the mutation was found has white wax in spite of the heterozygous genotype (G / A type). The mutation is therefore on the “normal” G allele and causes a loss of function there from the ABCC11 protein encoded from it, as is the case with the test person's A allele.

Earwax phenotype

Dry ear wax
Damp ear wax

There are two types of ear wax (cerumen) in humans : a dry, light-colored form with a high proportion of saturated fatty acids and a moist, yellow-brown form, with a high proportion of unsaturated fatty acids. The type of cerumen is genetic. The wet form is dominant compared to the dry form , or the dry form is recessive compared to the wet form. While the dry variant is very rare in the population of North America, Europe and Africa with less than 3 percent, its share in the population of East Asia is over 80%. The cause of the dimorphism in human ear wax is the single nucleotide mutation 538G → A in the ABCC11 gene. It determines the appearance and composition of the cerumen. The dominant mode of inheritance in accordance with the feature have the true-breeding (homozygous) G / G, and the heterozygous (heterozygous) G / A type of the wet form earwax. The dry form has only the homozygous A / A type, in which both alleles have the mutated form of the ABCC11 gene. In the heterozygous type, the loss of one allele is largely compensated for by the other, since the gene dose of the intact allele is sufficient to compensate for the loss of function. With the single nucleotide polymorphism 538G → A in ABCC11 , a DNA polymorphism was first discovered in 2005 that results in a visible genetic characteristic - the color and consistency of earwax. The antibacterial properties of the two types of cerumen are largely the same.

Body odor

Schematic representation of the ABCC11-related processes in an apocrine secretory cell. The ABCC11 protein (wild type, WT) derived from the G allele is glycosylated at positions Asn838 and Asn 844 in the endoplasmic reticulum (ER). After protein maturation in the Golgi apparatus , ABCC11 is transported to its destination, the membranes of granules , vesicles , vacuoles and the cell membrane. In contrast, the ABCC11 protein derived from the A allele is not glycosylated. Therefore, it misfolds what is detected by protein quality control, whereupon endoplasmic reticulum-associated degradation (ERAD) is initiated.

Humans have two types of sweat glands: eccrine and apocrine . While the eccrine sweat glands, which are distributed over the entire body, flow into the surface of the skin, the apocrine glands - also called scent glands - end in the hair follicles . As a result, the apocrine sweat glands are only found in certain hairy skin areas such as the armpits , the nipples , as well as in the genital and perianal area . The sweat produced by the two types of sweat glands differs significantly in its composition, but is largely odorless in both cases. However, the secretions of the apocrine sweat glands can be converted into odoriferous substances by bacteria , especially of the genera Corynebacterium and Staphylococcus . This gives each person a unique and characteristic body odor , which fulfills different, highly complex functions and thus influences, for example, physiology and behavior . The apocrine sweat glands are already created at birth, but only start their secretory activity at the onset of puberty. For this reason, too, it is assumed that the apocrine sweat glands make an important contribution to human social and sexual behavior . This is also assumed in non-verbal communication , for example through sweaty sweat . In contrast to colorless, watery eccrine sweat, apocrine sweat is milky, viscous in nature. The apocrine sweat contains, among other things, dehydroepiandrosterone-3-sulfate (DHEAS), androsterone sulfate, cysteinyl-glycyl-3-methylhexanol and short-chain, branched fatty acids that are conjugated with glutamine. These compounds are non- volatile and therefore odorless. But they are precursors ( precursors ) by the bacteria of the skin flora in volatile compounds in the example dehydroepiandrosterone , androsterone (both ARTIGEM urine with musky to odor), 3-methyl-3-sulfanylhexanol (onion-like smell) and the free short chain , branched fatty acids (sour-rancid smell) are broken down. Together with other metabolic products of bacteria, they are responsible for the bad smell of sweat. In general, body odor is rated negatively in the developed world. In addition to individual differences, there are also significant ethnic differences in body odor. In many Asian ethnic groups, the characteristic and intense body odor of people of European or African origin is hardly represented. A slightly acidic body odor predominates there. For example, the Japanese perceive the European-African odor pattern as unpleasant, which is why they used to refer to Europeans and Americans as bata-kusai (バ タ 臭 い, English: 'butter stinker') from around the 19th century . They suspected the consumption of butter by the Gaijins ('people from outside'), which was unusual in Japan at that time , as the cause of the “stench”. The term bata-kusai has undergone a change in Japan due to improved personal hygiene and the spread of deodorants . Today it is pejorative for things that are unpleasant or offensive to the West .

As early as 1937, a connection between the phenotype of ear wax (dry or damp) and body odor (weak or intense) was described in different ethnic groups. In fact, in 2009, genetic analysis found that it was the same genotype. The cause in both cases is the single nucleotide polymorphism 538G → A in the ABCC11 gene. The failure of the ABCC11 transporter is the reason that the precursors responsible for body odor can no longer be transported from the cytoplasm of the epithelial cells of the apocrine sweat glands into the vesicles for apocrine secretion and the bacteria of the skin flora do not form the fragrances from the precursors can. This is clearly shown experimentally in the composition of the sweat of the three genotypes. In a study with three genotype populations, the following values ​​were obtained:

molecule Genotype A / A Genotype G / A Genotype G / G
Fatty acid methyl ester
3-Hydroxy-3-methylhexanoic acid methyl ester 0.14 µg [*] 44.7 µg 45.8 µg
3-Hydroxy-4-methyloctanoic acid methyl ester 0.00 µg 1.84 µg 0.69 µg
( E ) -3-methyl-2-hexenoic acid methyl ester 0.02 µg > 2.8 µg > 2.8 µg
3-hydroxyhexanoic acid methyl ester 0.03 µg 0.08 µg 0.13 µg
3-Hydroxyoctanoic acid methyl ester 0.09 µg 1.29 µg 1.98 µg
free fatty acids
Butyric acid 0.61 µg 0.99 µg 1.27 µg
Isovaleric acid 0.08 µg 0.23 µg 0.76 µg
2-methylbutyric acid 0.23 µg 2.60 µg 12.9 µg
Caproic acid 1.37 µg 0.85 µg 1.07 µg
Caprylic acid 1.38 µg 0.77 µg 1.42 µg
Steroids
Dehydroepiandrosterone 2.04 ng / ml 94.3 ng / ml 131.7 ng / ml
Dehydroepiandrosterone sulfate 1.85 ng / ml 41.4 ng / ml 15.0 ng / ml
Androstenone 302.16 ng / ml 1070 ng / ml 1370 ng / ml
testosterone 0.24 ng / ml 0.33 ng / ml 0.46 ng / ml
Total protein 277 µg / ml 826 µg / ml 1041 µg / ml

[*] the mass values ​​refer to the amount from two cotton pads

In the sweat of the test persons with the A / A genotype - in contrast to the two other genotypes - there were no precursors based on amino acids, such as 3-hydroxy-3-methyl-hexanoic acid-Gln, ( E ) -3-methyl-2-hexenoic acid -Gln and 3-methyl-3-sulfanylhexan-1-ol-Cys-Gly detectable by LC / MS . From the data in the table it can be seen that the heterozygous G / A genotype produces fewer fragrances than the G / G genotype in most cases, but the gene dose is sufficient to absorb typical ABCC11 substrates in significantly larger quantities in the sweat than with the A / A genotype, in which the ABCC11 transporter is not present.

In a detailed analysis of a large-scale study of around 17,000 people in the County of Avon , England ( Avon Longitudinal Study of Parents and Children , ALSPAC), the frequency of deodorant use was correlated with the ABCC11 genotype. It turned out that people with the A / A genotype in the category “do not use deodorant” and “rarely use deodorant” with 22.2% compared to the G / A and G / G genotype (4.7 %) were almost five times overrepresented. Still, 77.8% of people of the A / A genotype used deodorants, even though it is largely pointless to them. The use of deodorants in these individuals is likely to be determined by socio-cultural factors. Deodorant use was significantly less in the heterozygous G / A genotype than in the G / G genotype.

With the knowledge gained at the beginning of the 21st century about the transport and metabolic processes of the ABCC11 substrates relevant for the sweat odor and the function of ABCC11, there are possible new starting points for the development of new types of deodorants. The Beiersdorf AG announced in 2008 at the German Patent and Trademark Office cosmetic preparations with an active ingredient "from the group of ABCC inhibitors" for the patent on. The inhibitors listed in the patent include, for example, the antidiabetic agent glibenclamide and the chemotherapeutic agent lonidamine . These active ingredients have very significant side effects that make their use in deodorants appear very unlikely. So far there is no deodorant with an ABCC11 inhibitor on the market (as of 2014). Beiersdorf withdrew the patent application in December 2013.

Colostrum and breast milk

Apocrine glands are found not only near hair follicles, but also in the female breast. This consists of the mammary gland ( mammary gland , glandula mammaria ) and a connective tissue-like stroma . The mammary gland develops from the systems of apocrine glands. Immediately after giving birth, a woman's mammary glands produce the first milk, called colostrum . In the colostrum it was possible to detect ingredients that correspond to those of apocrine sweat. They can also be found in the later breast milk, but in concentrations that are ten times lower. They could also be detected in the amniotic fluid . Overall, however, the concentrations are significantly lower than in apocrine sweat. These ingredients also get into these body fluids via the ABCC11 transporter. Several studies have shown that the smell of breast milk can stimulate an infant's sucking reflex. The apocrine secreted ingredients of colostrum, breast milk and amniotic fluid are subject to a very individual composition and concentration. The smell of these three body fluids is correspondingly individual. There is therefore the hypothesis that these individual differences may already have an impact on the mother in the embryo, or later in the infant, or that newborns can distinguish between the body fluids of their mother and another mother.

Mothers with the A / A genotype can produce less and less premilk ( colostrum ) through their mammary glands. In a Japanese study, 225 women were genotyped. 155 were A / A-homozygous and 70 G / A-heterozygous or G / G-homozygous. 67.7% of the women (= 105 people) of the A / A genotype had no colostrum formation, while this was only the case with 40% in the other group. The difference in the amount of colostrum formed was even clearer. In the 50 women of the A / A genotype who were able to produce colostrum, the average volume was 1.6 mL, while the group with at least one G allele produced 4.0 mL. It is still largely unclear what effects this has or could have on the nutrition of infants or even on evolutionary history.

Breast cancer risk

Breast cancer is the most common cancer in women in developed countries, accounting for around 22%. There are considerable regional differences. Breast cancer rates are significantly higher in western women than in Japanese and Taiwanese women. As early as 1971, the respected journal Science reported on a possible connection between a higher risk of breast cancer and a moist earwax phenotype. At that point, American women were four times more likely to develop breast cancer than Japanese women. In the years that followed, the correlation between cerumen phenotype and breast cancer risk was very controversial. More recent studies also provide contradicting results that assume a “significantly increased risk of breast cancer” for carriers of at least one G allele, and range up to “no increased risk”.

It is currently unclear whether the ABCC11 genotype really has an influence on the risk of breast cancer. The risk is probably only moderately increased - if at all - by the G alleles. In a study published in 2010, 270 Japanese breast cancer patients and 273 healthy volunteers were genotyped. Homozygous G / G patients were represented by a factor of 1.77 more frequently in the group of breast cancer patients. In heterozygous G / A patients, the value was 1.41.

The number of breast cancer cases in Japan has increased significantly over the past few decades and has roughly doubled since the 1970s. Changes in behavior, for example in diet, are essentially held responsible for this.

Population genetics

The A allele frequency in different populations
population frequency
African American
  
 0%
African
  
 2%
Latin American
  
 4%
Iberians
  
 10%
German
  
 16%
Western Europeans
  
 17%
Eastern Europeans
  
 20%
Pacific islanders
  
 21%
Kazakhs
  
 38%
Filipinos
  
 47%
Indians
  
 50%
Vietnamese
  
 73%
Japanese
  
 76%
Southeast Asians
  
 78%
Mongols
  
 87%
Chinese
  
 94%
Korean
  
 100%
Sources: and
World map of the distribution of the A allele of the single nucleotide polymorphism rs17822931 in the ABCC11 gene. The proportion of A alleles in the respective population is shown by the white area in each circle.

The frequency of the single nucleotide polymorphism 538G → A is subject to geographic dependency. In population genetics , one considers the allele frequency , which is a measure of the relative frequency of an allele in a population. A value of 0.20 means that 20% of the population has the corresponding allele in the genome. In Germany, according to a study with 132 test persons, around 16% of the population have at least one A allele. However, these 16% are essentially the heterozygous G / A type. According to the recessive inheritance, it has the same phenotype as the G / G type, i.e. yellow-brown, moist ear wax and body odor. The homozygous A / A type, with white, dry ear wax and very faint body odor, is much rarer. Its share is calculated from the square of the allele frequency. In the example of Germany this is 0.16² = 0.0256, which means that only about 2.6% of the population of Germany has the A / A genotype. The A allele frequency of ABCC11 is much higher in South Korea, for example . Depending on the study, it is between 0.98 and 1.0. Accordingly, over 96% of all Koreans have the A / A genotype. If members of other ethnic groups are cloned, one obtains a geographical distribution of the allele frequency of ABCC11 . This shows a clear increase in the east and north. In Africa, the “ cradle of mankind ”, the A allele frequency is extremely low. In nine studies with a total of 403 volunteers, there was not a single carrier of an A allele of ABCC11 . Only in one study carried out with 45 subjects from the Chagga people did one have an A allele.

Human intercontinental migration

The out-of-Africa theory , i.e. the assumption that the genus Homo spread over the whole world from its home continent Africa, is scientifically general due to several different indications, such as fossil finds, population genetics and linguistic geography for the species Homo sapiens accepted (see spread of man ). The routes of the primeval population flows to East , Central and Southeast Asia , as well as to the Arctic, America and Pacific islands have not yet been fully explored. Two routes have been proposed for this purpose: After the separation from the main stream formed with the inhabitants of Europe, North Africa and the Middle East, 150,000 to 60,000 years ago, they migrated to South Asia. It is assumed that a branch of this population flow settled there or migrated further in a south-east direction through Sundaland and finally reached Sahul - today's continent Australia - 50,000 to 46,000 years ago . In the last wave of migration 3000 to 1500 years ago, Oceania was finally settled. Another branch of the population of East, Central and Southeast Asia migrated north, reaching the area around Lake Baikal , along the Altai . As an alternative to this route, some may have migrated directly from the common mainstream to Siberia, or immigrated to Northeast Asia from Southeast Asia . It is also assumed that the glaciation during the last glacial maximum 30,000 to 15,000 years ago resulted in smaller tribes living largely isolated in the north.

It is now assumed that the single nucleotide polymorphism-induced mutation 538G → A probably occurred around 40,000 years ago in a tribe in primeval northern Mongolia. If one considers the north-south gradient in the distribution of the 538A allele with its maximum in northern China and Korea via Japan to Southeast Asia, then this probably reflects the migration of primeval northern Mongolian populations. The east-west gradient from Siberia to Europe, on the other hand, is due to significantly later waves of migration or invasion, such as the Mongol storm. A mutation in the mitochondrial ALDH2 gene, which codes for the enzyme aldehyde dehydrogenase 2, has a similar geographic distribution . The genetic defect is responsible for an increased sensitivity to alcohol in those affected.

Settlement of Japan

According to the current state of knowledge, Japan was populated by two waves of migration. The first wave took place after the last ice age, in the Jōmon period , about 13,000 to 3,000 years ago. The second wave of migration came during the Yayoi period , around 2500 to 1700 years ago. The Jōmon were either suppressed or assimilated by the Yayoi. One hypothesis is that the dry earwax genotype came to Japan from the Yayoi, while the moist type dominated among the Jōmon. This hypothesis is supported by the fact that the 538G genotype in remote areas - the retreat areas of the Jōmon - is significantly more common than in the Yoyoi areas. From this it can also be concluded that the genetic mixing of Jōmon and Yayoi in Japan is not yet complete.

From the frequency of the 538G allele and the associated moist earwax genotype it can be concluded that the Ainu , the natives of Japan, and the population of the Ryūkyū Islands (" Okinawa ") are not direct descendants of the Yayoi from northern Mongolia and Siberia came to Japan. Other studies have also come to the conclusion that the Ainu are genetically significantly different from other East Asian populations.

Selection advantage or gender drift

Schematic representation of a genetic bottleneck

It is largely unclear why the single nucleotide polymorphism 538G → A was able to spread so successfully in Asia. There are currently two different explanations for this. One approach is based on a selection advantage for the A / A genotype, the other on a genetic drift .

With a large population, there must be an extremely high selection pressure so that a mutation can successfully establish itself in a comparatively short time. In the case of the A / A genotype, it is difficult to imagine a selection advantage over the composition of the earwax. It is more likely that another single nucleotide polymorphism rs6500380 in the LONP2 gene, which has a strong coupling imbalance to rs17822931 (r² = 0.91) and therefore occurs very often together in the corresponding populations, offers the selection advantage. LONP2 codes for the enzyme peroxisomal LON protease homolog 2 . According to the current state of knowledge, however, rs6500380 has a significantly lower functional significance than rs17822931, so that a possible selection advantage very likely comes from rs17822931. Among other things, this could result from the fact that the A / A genotype of the prehistoric population of Northeast Asia was able to better adapt to the considerably colder climate of the region due to the lower perspiration. It is also possible that the change in the composition of the colostrum or a still unknown dysfunction of ABCC11 in other tissues, such as testes, liver, placenta, lungs or brain, in which ABCC11 is also expressed, offered a selection advantage. The most plausible at present seems to be the hypothesis of an advantage in sexual selection . Eastern cultures by the past had - compared to those in the west - a much more pronounced tradition of cleanliness and hygiene. The low-odor A / A genotype possibly had a significant advantage when choosing a partner over the 'stronger smelling' G / G or G / A genotype. A hypothesis that seems plausible, at least from today's perspective, in which intense body odor is also perceived as socially offensive in Western cultures. Simulation calculations from 2011 come to the result that the mutation of rs17822931-A took place around 2006 generations ago, with a confidence interval of 95% in the range from 1023 to 3901 generations. A selection coefficient of 0.01 was assumed for this.

Assuming rather small populations, completely different evolutionary effects than the selection pressure can lead to sudden and massive changes in the frequency of a genotype in subsequent generations. The inherited mutations are not subject to selection. They are neutral, that is, they have no effect on the fitness of the phenotype ( survival of the fittest ). This form of shifting the allele frequency , i.e. the frequency of an allele in a population, is called gene drift. The 'success' of a mutation depends on the size of the population and the selection pressure. Genetic drift and selection are evolutionary factors that work simultaneously. In large populations, selection dominates, in small populations, genetic drift. The genetic drift is a statistical, random effect that is favored by small populations. Small, self-contained populations represent a genetic bottleneck . This can be caused, for example, by strong climatic changes, epidemics or famine. But less dramatic changes, such as the migration of a few individuals from a large population, the so-called founder effect , can lead to a genetic bottleneck. This can result in allele frequencies that contradict natural selection. A genetic bottleneck and an associated genetic drift is also discussed as a possible cause for the successful distribution of the A / A genotype.

Footnotes

  1. ↑ Genome Reference Consortium human genome (build 37)
  2. ↑ There are also study results that come to the conclusion that the functionless ABCC11 variant Gly180Arg is nevertheless expressed on the cell membrane (see Annette Martin, Matthias Saathoff, Fabian Kuhn, Heiner Max, Lara Terstegen, Andreas Natsch: A functional ABCC11 allele is essential in the biochemical formation of human axillary odor . In: Journal of Investigative Dermatology . Volume 130 , no. 2 , 2010, p. 529-540 , doi : 10.1038 / jid.2009.254 , PMID 19710689 . ).

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