Missing heritability problem

6:10 PM | BY ZeroDivide EDIT

The "missing heritability" problem[1][2][3][4][5][6] is the fact that single genetic variations cannot account for much of the heritability of diseases, behaviors, and other phenotypes. This is a problem that has significant implications for medicine, since a person's susceptibility to disease may depend more on 'the combined effect of all the genes in the background than on the disease genes in the foreground', or the role of genes may have been severely overestimated.

The 'missing heritability' problem was named as such in 2008 (after the "missing baryon problem" in physics). The Human Genome Project led to optimistic forecasts that the large genetic contributions to many traits and diseases (which were identified by quantitative genetics and behavioral genetics in particular) would soon be mapped and pinned down to specific genes and their genetic variants by methods such as candidate-gene studies which used small samples with limited genetic sequencing to focus on specific genes believed to be involved, examining the SNP kinds of variants. While many hits were found, they often failed to replicate in other studies.

The exponential fall in genome sequencing costs led to the use of GWAS studies which could simultaneously examine all candidate-genes in larger samples than the original finding, where the candidate-gene hits were found to almost always be false positives and only 2-6% replicate;[7][8][9][10][11][12] in the specific case of intelligence candidate-gene hits, only 1 candidate-gene hit replicated,[13] the top 25 schizophrenia candidate-genes were no more associated with schizophrenia than chance,[14][15] and of 15 neuroimaging hits, none did.[16] The editorial board of Behavior Genetics noted, in setting more stringent requirements for candidate-gene publications, that "the literature on candidate gene associations is full of reports that have not stood up to rigorous replication...it now seems likely that many of the published findings of the last decade are wrong or misleading and have not contributed to real advances in knowledge".[17] Other researchers have characterized the literature as having "yielded an infinitude of publications with very few consistent replications" and called for a phase out of candidate-gene studies in favor of polygenic scores.[18]

This led to a dilemma. Standard genetics methods have long estimated large heritabilities such as 80% for traits such as height or intelligence, yet none of the genes had been found despite sample sizes that, while small, should have been able to detect variants of reasonable effect size such as 1 inch or 5 IQ points. If genes have such strong cumulative effects - where were they? Several resolutions have been proposed, that the missing heritability is some combination of:

  1. Twin studies and other methods were grossly biased by issues long raised by their critics; there was little genetic influence to be found. Therefore, it has been proposed that the genes that supposedly underlie behavior genetic estimates of heritability simply do not exist.[19]
  2. Genetic effects are actually epigenetics
  3. Genetic effects are generally non-additive and due to complex interactions. Among many proposals, a model has been introduced that takes into account epigenetic inheritance on the risk and recurrence risk of a complex disease.[4] The limiting pathway (LP) model has been introduced in which a trait depends on the value of k inputs that can have rate limitations due to stoichiometric ratios, reactants required in a biochemical pathway, or proteins required for transcription of a gene. Each of these k inputs is a strictly additive trait that depends on a set of common or rare variants. When k = 1, the LP model is simply a standard additive trait.[2]
  4. Genetic effects are not due to the common SNPs examined in the candidate-gene studies & GWASes, but due to very rare mutations, copy-number variations, and other exotic kinds of genetic variants. These variants tend to be harmful and kept at low frequencies by natural selection. Whole-genome sequencing would be required to track down specific rare variants.
  5. Traits are all misdiagnoses: one person's 'schizophrenia' is due to entirely different causes than another schizophrenic, and so while there may be a gene involved in 1 case, it will not be involved in another, rendering GWASes futile
  6. GWASes are unable to detect genes with moderate effects on phenotypes when those genes segregate at high frequencies[20]
  7. Traits are genuine but inconsistently diagnosed or genetically influenced from country to country and time to time, leading to measurement error, which combined with genetic heterogeneity, either due to race or environment, will bias meta-analyzed GWAS & GCTA results towards zero,[21][22][23][24][25][26]
  8. Genetic effects are indeed through common SNPs acting additively, but are highly polygenic: dispersed over hundreds or thousands of variants each of small effect like a fraction of an inch or a fifth of an IQ point and with low prior probability: unexpected enough that a candidate-gene study is unlikely to select the right SNP out of hundreds of thousands of known SNPs, and GWASes up to 2010, with n<20000, would be unable to find hits which reach genome-wide statistical-significance thresholds. Much larger GWAS sample sizes, often n>100k, would be required to find any hits at all, and would steadily increase after that.
This resolution to the missing heritability problem was supported by the introduction of Genome-wide complex trait analysis (GCTA) in 2010, which demonstrated that trait similarity could be predicted by the genetic similarity of unrelated strangers on common SNPs treated additively, and for many traits the SNP heritability was indeed a substantial fraction of the overall heritability. The GCTA results were further buttressed by findings that a small percent of trait variance could be predicted in GWASes without any genome-wide statistically-significant hits by a linear model including all SNPs regardless of p-value; if there were no SNP contribution, this would be unlikely, but it would be what one expected from SNPs whose effects were very imprecisely estimated by a too-small sample. Combined with the upper bound on maximum effect sizes set by the GWASes up to then, this strongly implied that the highly polygenic theory was correct. Examples of complex traits where increasingly large-scale GWASes have yielded the initial hits and then increasing numbers of hits as sample sizes increased from n<20k to n>100k or n>300k include height,[27] intelligence,[28] and schizophrenia.

sex-determination system

9:27 PM | BY ZeroDivide EDIT
Different types of sex determination depending on chromosomes.
A sex-determination system is a biological system that determines the development of sexual characteristics in an organism. Most sexual organisms have two sexes. Occasionally, there are hermaphrodites in place of one or both sexes. There are also some species that are only one sex due to parthenogenesis, the act of a female reproducing without fertilization.
In many species, sex determination is genetic: males and females have different alleles or even different genesthat specify their sexual morphology. In animals this is often accompanied by chromosomal differences, generally through combinations of XY, ZW, XO, ZO chromosomes, or haplodiploidy. The sexual differentiation is generally triggered by a main gene (a "sex locus"), with a multitude of other genes following in a domino effect.
In other cases, sex is determined by environmental variables (such as temperature) or social variables (e.g. the size of an organism relative to other members of its population). Environmental sex determination preceded the genetically determined systems of birds and mammals; it is thought that a temperature-dependent amniote was the common ancestor of amniotes with sex chromosomes.[citation needed]
Some species do not have a fixed sex, and instead change sex based on certain cues. The details of some sex-determination systems are not yet fully understood.

Chromosomal determination[edit]

XX/XY sex chromosomes[edit]

Drosophila sex-chromosomes
Main article: XY sex-determination system
The XX/XY sex-determination system is the most familiar, as it is found in humans. In the system, females have two of the same kind of sex chromosome (XX), while males have two distinct sex chromosomes (XY). The XY sex chromosomes are different in shape and size from each other, unlike the autosomes, and are termed allosomes. Some species (including humans) have a gene SRY on the Y chromosome that determines maleness; others (such as the fruit fly) use the presence of two X chromosomes to determine femaleness.[1] Because the fruit fly, as well as other species, use the number of Xs to determine sex, they are nonviable with an extra X. SRY-reliant species can have conditions such as XXY and still live.[2] Human sex is determined by containing SRY or not. Once SRY is activated, cells create testosterone and anti-müllerian hormone to turn the genderless sex organs into male.[2] With females, their cells excrete estrogen, driving the body down the female pathway. Not all organisms remain gender indifferent for a time after they're created; for example, fruit flies differentiate into specific sexes as soon as the egg is fertilized.[2] In Y-centered sex determination, the SRY gene is not the only gene to have an influence on sex. Despite the fact that SRY seems to be the main gene in determining male characteristics, it requires the action of multiple genes to develop testes. In XY mice, lack of the gene DAX1 on the X chromosome results in sterility, but in humans it causes adrenal hypoplasia congenita.[3] However, when an extra DAX1 gene is placed on the X, the result is a female, despite the existence of SRY.[4] Also, even when there are normal sex chromosomes in XX females, duplication or expression of SOX9 causes testes to develop.[5][6] Gradual sex reversal in developed mice can also occur when the gene FOXL2 is removed from females.[7] Even though the gene DMRT1 is used by birds as their sex locus, species who have XY chromosomes also rely upon DMRT1, contained on chromosome 9, for sexual differentiation at some point in their formation.[2]
The XX/XY system is also found in most other mammals, as well as some insects. Some fish also have variants of this, as well as the regular system. For example, while it has an XY format, Xiphophorus nezahualcoyotl and X. milleri also have a second Y chromosome, known as Y', that creates XY' females and YY' males.[8] At least one monotreme, the platypus, presents a particular sex determination scheme that in some ways resembles that of the ZW sex chromosomes of birds, and also lacks the SRY gene, whereas some rodents, such as several Arvicolinae (voles and lemmings), are also noted for their unusual sex determination systems. The platypus has ten sex chromosomes; males have an XYXYXYXYXY pattern while females have ten X chromosomes. Although it is an XY system, the platypus' sex chromosomes share no homologues with eutherian sex chromosomes.[9] Instead, homologues with eutherian sex chromosomes lie on the platypus chromosome 6, which means that the eutherian sex chromosomes were autosomes at the time that the monotremes diverged from the therian mammals (marsupials and eutherian mammals). However, homologues to the avian DMRT1 gene on platypus sex chromosomes X3 and X5 suggest that it is possible the sex-determining gene for the platypus is the same one that is involved in bird sex-determination. More research must be conducted in order to determine the exact sex determining gene of the platypus.[10]
Heredity of sex chromosomes in XO sex determination

XX/X0 sex determination[edit]

Main article: X0 sex-determination system
In this variant of the XY system, females have two copies of the sex chromosome (XX) but males have only one (X0). The 0 denotes the absence of a second sex chromosome. Generally in this method, the sex is determined by amount of genes expressed across the two chromosomes. This system is observed in a number of insects, including the grasshoppers and crickets of order Orthoptera and in cockroaches (order Blattodea). A small number of mammals also lack a Y chromosome. These include the Amami spiny rat (Tokudaia osimensis) and the Tokunoshima spiny rat (Tokudaia tokunoshimensis) and Sorex araneus, a shrew species. Transcaucasian mole voles (Ellobius lutescens) also have a form of XO determination, in which both genders lack a second sex chromosome.[4] The mechanism of sex determination is not yet understood.[11]
The nematode C. elegans is male with one sex chromosome (X0); with a pair of chromosomes (XX) it is a hermaphrodite.[12] Its main sex gene is XOL, which encodes XOL-1 and also controls the expression of the genes TRA-2 and HER-1. These genes reduce male gene activation and increase it, respectively.[13]

ZW sex chromosomes[edit]

Main article: ZW sex-determination system
The ZW sex-determination system is found in birds, some reptiles, and some insects and other organisms. The ZW sex-determination system is reversed compared to the XY system: females have two different kinds of chromosomes (ZW), and males have two of the same kind of chromosomes (ZZ). In the chicken, this was found to be dependent on the expression of DMRT1.[14] In birds, the genes FET1 and ASW are found on the W chromosome for females, similar to how the Y chromosome contains SRY.[2] However, not all species depend upon the W for their sex. For example, there are moths and butterflies that are ZW, but some have been found female with ZO, as well as female with ZZW.[12] Also, while mammals inactivate one of their extra X chromosomes when female, it appears that in the case of Lepidoptera, the males produce double the normal amount of enzymes, due to having two Z's.[12] Because the use of ZW sex determination is varied, it is still unknown how exactly most species determine their sex.[12] However, reportedly, the silkworm Bombyx mori uses a single female-specific piRNA as the primary determiner of sex.[15] Despite the similarities between ZW and XY, the sex chromosomes do not line up correctly and evolved separately. In the case of the chicken, their Z chromosome is more similar to humans' autosome 9.[16] The chicken's Z chromosome also seems to be related to the X chromosomes of the platypus.[17] When a ZW species, such as the Komodo Dragon, reproduce parthenogenetically, usually only males are produced. This is due to the fact that the haploid eggs double their chromosomes, resulting in ZZ or WW. The ZZ become males, but the WW are not viable and are not brought to term.[18]

UV sex chromosomes[edit]

In some Bryophyte and some algae species, the gametophyte stage of the life cycle, rather than being hermaphrodite, occurs as separate male or female individuals that produce male and female gametes respectively. When meiosis occurs in the sporophyte generation of the life cycle, the sex chromosomes known as U and V assort in spores that carry either the U chromosome and give rise to female gametophytes, or the V chromosome and give rise to male gametophytes.[19]
Haplodiploid sex chromosomes

Haplodiploidy[edit]

Main articles: Ploidy and Haplodiploidy
Haplodiploidy is found in insects belonging to Hymenoptera, such as ants and bees. Unfertilized eggs develop into haploid individuals, which are the males. Diploid individuals are generally female but may be sterile males. Males cannot have sons or fathers. If a queen bee mates with one drone, her daughters share ¾ of their genes with each other, not ½ as in the XY and ZW systems. This is believed to be significant for the development ofeusociality, as it increases the significance of kin selection, but it is debated.[20] Most females in the Hymenoptera order can decide the sex of their offspring by holding received sperm in their spermatheca and either releasing it into their oviduct or not. This allows them to create more workers, depending on the status of the colony.[21]

Non-genetic sex-determination systems[edit]

All alligators determine the sex of their offspring by the temperature of the nest.

Temperature-dependent sex determination[edit]

See also: Temperature-dependent sex determination
Many other sex-determination systems exist. In some species of reptiles, including alligators, some turtles, and the tuatara, sex is determined by the temperature at which the egg is incubated during a temperature-sensitive period. There are no examples of temperature-dependent sex determination (TSD) in birds. Megapodes had formerly been thought to exhibit this phenomenon, but actually exhibit temperature-dependent embryo mortality.[22] For some species with TSD, sex determination is achieved by exposure to hotter temperatures resulting in the offspring being one sex and cooler temperatures resulting in the other. For others species using TSD, it is exposure to temperatures on both extremes that results in offspring of one sex, and exposure to moderate temperatures that results in offspring of the opposite sex. These systems are known as Pattern I and Pattern II, respectively. The specific temperatures required to produce each sex are known as the female-promoting temperature and the male-promoting temperature.[23] When the temperature stays near the threshold during the temperature sensitive period, the sex ratio is varied between the two sexes.[24]Some species' temperature standards are based on when a particular enzyme is created. These species that rely upon temperature for their sex determination do not have the SRY gene, but have other genes such as DAX1, DMRT1, and SOX9 that are expressed or not expressed depending on the temperature.[23] The sex of some species, such as the Nile Tilapia, Australian skink lizard, and Australian dragon lizard, is initially determined by chromosomes, but can later be changed by the temperature of incubation.[8]
It is unknown how exactly temperature-dependent sex determination evolved.[25] It could have evolved through certain sexes being more suited to certain areas that fit the temperature requirements. For example, a warmer area could be more suitable for nesting, so more females are produced to increase the amount that nest next season.[25]

Other sex-determination systems[edit]

Although temperature-dependent sex determination is relatively common, there are many other environmental systems. Some species, such as somesnails, practice sex change: adults start out male, then become female (See also sex reversal). In tropical clown fish, the dominant individual in a group becomes female while the other ones are male, and bluehead wrasses (Thalassoma bifasciatum) are the reverse. In the marine worm (Bonellia viridis), larvae become males if they make physical contact with a female, and females if they end up on the bare sea floor. This is triggered by the presence of a chemical produced by the females, bonellin. Some species, however, have no sex-determination system. Hermaphrodite species include the common earthworm and certain species of snails. A few species of fish, reptiles, and insects reproduce by parthenogenesis and are female altogether. There are some reptiles, such as the boa constrictor and komodo dragon that can reproduce both sexually and asexually, depending on whether a mate is available.[26]
Other unusual systems:

Evolution of sex-determination systems[edit]

Origin of sex chromosomes[edit]

The ends of the XY chromosomes, highlighted here in green, are all that is left of the original autosomes that can stillcross-over with each other.
The accepted hypothesis of XY and ZW sex chromosome evolution is that they evolved at the same time, in two different branches.[27][28] However, there is some evidence to suggest that there could have been transitions between ZW and XY, such as in Xiphophorus maculatus, which have both ZW and XY systems in the same population, despite the fact that ZW and XY have different gene locations.[29][30] A recent theoretical model raises the possibility of both transitions between the XY/XX and ZZ/ZW system and environmental sex determination[31] The platypus' genes also back up the possible evolutionary link between XY and ZW, because they have the DMRT1 gene possessed by birds on their X chromosomes.[32]Regardless, XY and ZW follow a similar route. All sex chromosomes started out as an original autosome of an original amniote that relied upon temperature to determine the sex of offspring. After the mammals separated, the branch further split into Lepidosauria and Archosauromorpha. These two groups both evolved the ZW system separately, as evidenced by the existence of different sex chromosomal locations.[28] In mammals, one of the autosome pair, now Y, mutated its SOX3gene into the SRY gene, causing that chromosome to designate sex.[28][32][33] After this mutation, the SRY-containing chromosome inverted and was no longer completely homologous with its partner. The regions of the X and Y chromosomesthat are still homologous to one another are known as the pseudoautosomal region.[34] Once it inverted, the Y chromosome became unable to remedy deleterious mutations, and thus degenerated.[28] There is some concern that the Y chromosome will shrink further and stop functioning in 10 million years, but other evidence has shown that the Y chromosome has been strictly conserved after its initial rapid gene loss.[35][36]
There are some species, such as the medaka fish, that evolved sex chromosomes separately; their Y chromosome never inverted and can still swap genes with the X. These species are still in an early phase of evolution with regard to their sex chromosomes. Because the Y does not have male-specific genes and can interact with the X, XY and YY females can be formed as well as XX males.[8]

See also[edit]

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