Mendelian Inheritance in Man (OMIM): (database of human genetic diseases and genetic variants)

See also DNA

Introduction/Definitions:

When defining the number of chromosomes necessary to define  a species, geneticits count the haploid (n) number of chromosomes. For humans and many other species, the total number of chromosomes in a cell is called the diploid (2n) number, which is twice the hapoid number. For humans, the haploid number is 23 and the diploid number is 46. Diploid chromosomes reflect the equal genetic contribution that each parent makes to offspring. Materal and paternal chromosomes are referred to as being homologus, and each oe of the pair is termed a homologue.

Humans have 23 paired chromosomes. 22 of these pairs are non-sex (autosomes or chromosomes inherited symmetrically from both parents, regardless of sex) and 1 pair are sex chromosomes (X and Y in males and XX in females) to bring the total number of chromosomes in a human somatic (non-germ line) to a total of 46. Thus at conception, every human inherits a half set of her mother’s genetic information, consisting of 23 chains of DNA with 20k genes, and also a half set of her father’s genetic information, consisting of another 23 chains of DNA 20k genes. During gestation, that information is conveyed into every cell in the humn being’s body and thus results in two instances of every gene. 

Chromosomes have two arms, the so called long arm (“q”) and the short arm (“p) which are separated by a centromere.

Although the Mendelian model explains a lot of inheritance, there are exceptions. Primiarly, these are due to the presence of DNA in organelle genomes, specifically mitochondria and chloroplasts. Another prominent exception found in flowering plants and mammals involves parent of origin effects called imprinting. 

Organisms also generally have many more genes that assort independently than the number of chromosomes. This means that independent assortment cannot be due only to the random alignment of different chromosomes during meiosis. The reason for this is crossing over of homologues during meiosis. 

Gene 

a Gene is any DNA sequence that is transcribed as a single unit and encodes one set of closely related polypeptide chains. In eucaryotes, protein coding genes are usually composed of a string of alternating introns (non-coding regions) and exons (coding regions). The complete set of information contained in an organism’s DNA is sometimes called its “genome”. In humans, the genome is about 20,000-30,000 proteins since our DNA is capable of coding for that many proteins. Humans, mice and puffer fish all have about the same number of genes. Thus, organismal complexity is not a simple funcito of either genome size or gene number. DNA in humans is distributed over 24 different chromosomes.

Allele: 

An allele is one of a pair, or series, of forms of a gene or non-geneic region that occur at a given locus in a chromosome. Alleles are symbolized with the same basic symbol (e.g., B for dominant and b for recessive; B1, B2, Bn for n additive alleles at a locus). In a normal diploid cell there are two alleles of any one gene (one from each parent), which occupy the same relative position (locus) on homologous chromosomes. Within a population there may be more than two alleles of a gene. Small nucleotide polymorphisms (SNPs) also have alleles (i.e., the two (or more) nucleotides that characterize the SNP.

Alleles do not always have a clear dominant and recessive relationship; in some cases, alleles can be co-dominant, meaning both alleles are expressed equally in the phenotype, and neither is considered dominant over the other. In humans, for example, the A and B alleles for blood type are codominant, so someone with one A allele and one B allele will have blood type AB.

The existence of small RNAs encoded by dominant alleles have been shown to prevent the expression of recessive alleles. In one model, a small RNA encoded by the frist allele recognises a specific sequence on the second allele and blocks its expression. (“Dominant and recessive gene expression, chapter Two: the molecualr mechanism for dominance”. Agroecology, December 17, 2014)

Introns: 

Introns are non-coding regions of the DNA. Traditionally they were referred to as “junk DNA” because at least historically they appeared to serve no function.  US Patent No. 5,612,179 discloses that certain DNA sequences in coding reigons (exons) of certain genes are correlated with non-coindg regions (introns) within the same gene, non-coding regions in different genes, or non-coding regions of the genome that are not part of any gene. The correlated coding and non-coding regions tend to be inherited together, with only rare shuffling. In other words, the regions are in “linkage disequilibrium” meaning that the coding and non-coidng regions appear “linked” together in individuals’ genomes more often that probability would dictate. Linkdage disequilibrium is a condition in which certain alleles at two linked loci are non-randomly assocaited with each other. The correlated coding and non-coding regions may be linked even though the two sequences are located far apart form one another on the chromosome. 

GeneMaps: are defined as groups of gene(s) that are directly or indirectly involved in at least one phenotype of a trait.

Genotype: set of alleles at a specified locus or loci.

Epigentic inheritance: An epigentic change is defined as a mitotically and/or meiotically stable change in gene funciton that does not involve a change in DNA sequence. An example is X-chromosome inactivation (see below) where an entire chromosome is silenced, and the effect is inherited through many mitotic dividsions. In some mouse and rat models, this even includes effects of materianl diet on F2 animals. 

Epigenetic mechniasms include changes in DNA methylation and histone modifications. Noncoding RNAs and nuclear organization have aso been implicated. Alternations in chromatin structure and the accessibility of DNA seem to be a point of convergence for multiple epigentic mechanisms. 

–Genomic impriting: is an example of epigenetic inheritance.  In genomic imprinting, the phenotype caused by a mutant allele is exhibited when the allele comes form one parent, but not when it comes from the other. Some imprinted genes are inactivated in the paternal germ line and therefore not expressed in the zygote. Other imprinted genes are inactivated in the maternal germ line, with the same result. This makes the zygote effectively haploid for an imprinted gene, and thus the effect of mutant alleles depends on the parent of origial Imprinted genes also seem to be concenetrated in particular regions of the genome, with genes that are both maternally and paternally imprinted. 

An example of genetic imprinting the igf 2 gene in the mouse. Mutant igf 2 leads to dwarf mice. However, only the paternal allele is expressed. Thus when normal mice (homozygous, green normal) were crossed with drawf mice (red homozygous for a recessive mutant allele of igf2), the phenotypes of the hterozygous offspring were deifferent depending on which parent contirbuted the mutant allele. For example, a paternal (green) with materinal red mutant mouse would appear normal since the maternal mutant allele is not expressed. However, a paternal red with materinal green would appear drarf since materinal green is not expressed. 

Haplotype: The allelic pattern of a group of (usually contiguous) DNA markers or other polymorphic loci along an individual chromosome or double helical DNA segment. Haplotypes identify individual chromosomes or chromosome segments. The presence of shared haplotype patterns amoung a group of individuals implies that the locus defined by the haplotype has been inerited, identical by descent froma common ancestor. Detection of identical by descent haplotypes is the basis of linkage disequilibrium (LD) mapping.

Noncoding DNA: A huan gene is made up of numerous pieces of coding DNA (exons) interspeersed with lenghs of noncoding DNA (introns). Introns comprise about 24% of the human genome, whereas the exons comprise less than 1.5%. However, this noncoding DNA is important. MicroRNA genes (miRNA), for example, are hidden in the noncoding DNA. Tehy are a mechanism for controlling gene expression. Long, noncoding RNA is also not translated into protein but serve a regulatory role and likely regulate gene expression. 

sex-linked or X-linked: A trait determined by a gene on the X chromosome is said to be sex-linked or X-linked because it will segragate with the sex chromosomes. From ancient times, people noted conditions taht seem to affect males to a greater degree than females. This can be explained if the genes responsbiel are located on the X chromosome. Red-green color blindness for example is a condition that is more common in males becasue the gene affected is carried on the X chromosome. Anotehr example is hemophilia, a disease that affects a single protein in a casade of proteins involved in the formation of blood clots. 

Dosage compensation, epistasis and X inactivation: Although males have only one X chromosome and females have two, female cells do not produce twice the amount of the proteins encoded by genes on the X chromosome. Instead, one of the X chromosomes in females is inactivated early in embronic devellpment, shortly after the embryo’s sex is determined. This inactivation is an example of dosage compensation which ensures an equal level of expression from the sex chromosomes despite a differing number of sex chromosomes in males and females. In Drosophila, by contrast, dosage compensation is acheived by increasing the level of expression on the male X chromosome. Which X chromosome is inactivated in human females varies randomly from cell to cell. If a female is heterozygous for a sex linked trait, some of the cells will express one allele and some the other. Females that are heterozgous for X chromosome alleles are genetic mosaics in that their individual cells may express different alleles depending on which chromosome is inactivated. The calico cat, for example, is a female that has a patchy distribution of dark fur, organge fur and white fur. The dark fur and organe fur are due to heterozygosity for a gene on the X chromosome that detemrines pigment color. One allele results in dark fur, and another allele results in organe fur. Which of these colors is observed in any particular patch is due to inactivaiton of one X chromosome. If the chromosome containing the organe allele is inactivated, then the fur will be dark and vice versa. The patchy distribution of colr, and the presence of white fur, is due to a second gene that is epistatic to the fur color gene. That is, the presence of this second gene produces a patchy distribution of pignment with some areas totally lacking pignment. In the areas that lack pigment, the effect of either fur color allele is masked. This is an example of both epistasis and X inactivation. 

Maternal Inheritance: is a mode of uniparental (one-parent) inheritance form the mother. For example, organelles are usually inherited from usually the mother. When a zygote is formed, it received an equal contribution of the nuclear genome from each parent, but it gets all of the mitochondia from the egg cell, which contains a great deal more cytoplasm and thus organelles. As the zygote divides, these original mitchondia divide as well and are partitioned randomly. As a result, the mitochondria in every cell of an adult organism can be traced back tot he original maternal mitochondia present in the egg. 

In humans, the diease Leber’s hereditary optic neuropathy shows maternal inheritance. The genetic basis of this disease is a mutant allele for a subunit of NADH dehydrogenase. The mutant allele reduces the efficiency of electron flow in the elctron transport chain in mitochondria, in turn reducing overall ATP produciton. Some nerve cells in the optic system are particularly sensitive to reduction in ATP production, resulting in neural degeneration. A mother with this disease will pass it on to all of ther progency, whereas a father wih the disease will not pass it on to any of this progeny. Note that unlike ex-linked inheritance above, in maternal inheritance males and females are equally affected. 

Crossing over of homologues during Meiosis: In prophase I of meiosis, homologues appear to physically exchange material by crossing over. As the distance separating loci increases, the probability of recombination occurring between them during meiosis also increases. Genetic maps are constructed based on recombination frequency. 1 map unit is 1% recombinant progeny. 

Short tandem repeats (STRs): are short repeats of 2-4 bases that can differ in repeat number between individuals. These have been sued in genetic mapping, and also form the basis for databases used in forensic anlysis of DNA. 

Single-nucleotide polymorphisms (SNPs): Using data form sequencing the human genome allows the identificaiton and mapping of single base differences between individuals. Any differences between individuals in populations are termed polymorphisms: polymorphisms affecting a single base of a gene locus are called SNPs. It is possible to start with a complex disease phenotype, for example, coronary artery disease, then look for SNPs assocaiated with this phenotype in a population. As the locaiton of each SNP is known, one can then look for candidate genes in that region of the genome. This is an example of forward genetics, going from a known phenotype to an unknown genotype. There are over 650 million SNV entries in a databse devoted to genetic variation. There is also massive variation in short repetitive regions that difficult to sequence accurately. 

DNA fingerprinting uses short tandem repeats (STRs) that vary in number between individuals. The CODIS database stores data on 13 different STR loci. 

Chromosome Structure:

Each chromosome consists of a long DNA molecule associated with proteins that fold the DNA into a more compact structure. This complex of DNA and protein is sometimes referred to as chromatin. The proteins that bind to the DNA are typically referred to as the histones and the nonhistone proteins.

Chromatin is organized into nucleosomal subunits. Each nucleosome consists of 146 bp of DNA wrapped around two molecules each of the histone proteins H2A, H2B, H3 and H4 and a single linker protein, H1. Histones are responsible for the most basic level of chromosome organization, the nucleosome, which is DNA and histone proteins. Histone dimers form a compact octamer core.  The lenght of the DNA wound around the core has been shown to be about 150 nucleotide pairs wrapped twice around 8 histone molecules (two each of H2A, H2B, H3, and H4). Nucleosomes are separated by about 50 bp of DNA.

Many hydrogen bonds are formed between DNA (phosphodiester backbone) and the histone core (amino acid backbone). Numerous hydrophobic interactions interactions also hold DNA and protein together in the nucleosome. All the core histones are rich in lysine and arginine (2 amino acids with basic side chains) and their positive charges can neutralize the negatively charged DNA backbone. Each of the core histones has a long N-terminal amino acid tails which extends out from the DNA-histone core. The N-terminal tails of each of the histones are subject to different types of covalent modification which are crucial in regulating chromatin structure which can regulate gene expression. The domains are lysine rich are are targets of a class of enzymes termed histone acetyl transferases.

Although long strings of nucleosomes form on most chromosomal DNA, chromatin in a cell probably rarely adopts an extended beads on a string form. Instead, it is seen to be in the form of a fiber about 30 nm thick. This represents nucleosomes which are packed on top of one another, generating arrays in which the DNA is even more condensed. Such highly packed chromatin is sometimes referred to as euchromatin. The 30 nm euchromatin is not conducive to transcription (2nm and 11 nm would be compatible).

There is even a more condensed form of chromatin that is sometimes called heterochromatin which is included in certain regions of the chromosomes such as the telemores and centromeres. Covalent modification of the nucleosome core histones as by methylation of specifc lysines by histone methl transferases play a critical role in the formation of heterochromatin. One protein, Sir2, also has a role in creating a pattern of histone underacetylation unique to heterchromatin.

Sex chromosomes: 

In males, the single X chromosome paris in meiosis with a disimilar partner called the Y Chromosome. The X and Y chromosomes are terms sex chromosomes because of their association with sex. The defulat setting in human embronic development leads to female development. Some of the active genes of the Y chromosome are responsible for the masculinization of genitalia and secondary sex organs, producing features, associated with “maleness” in humans. Consequently, any individual with at last one Y chromosome is normally male. In vertebrates, this form of sex determination is seen in mammals and birds and is called chromosomal sex determination.

The structure and number of sex chromosomes vary in idfferent species. In the fruit fly, Drosophila, females are XX and males XY, which is also the case for humans and other mammals. However, in birds, the male has two Z chromosemes, and the female has a Z and a W chromosome. Some insects, such as grasshoppers, have no Y chromosome; females are XX and males are characterized as XO (O indicates the absence of a chromosome)

Humans have 46 chrosomes (23 paris). One pair consists of the sex chromosomes, which are dissiimilar wehreas the other 22 paris, which are similar are called autosomes. 

The Y chromosome in males is highly condensed. Becasue few genes on the Y chromosome are expressed, recessive alleles on a male’s single X chromosome have not active counterpart of the Y chromosome. 

Although males have only one X chromosome and females have two, female cells do not produce twice the amount of the proteins encoded by genes on the X chromosome. Instead, one of the X chromosomes in females is inactivated early in embryonic development, shortly after the embryo’s sex is determeind. Tis inactivaiton is an example of dosage compensation, which ensures an equal level of expression from the sex chromsomes despite a differing number of sex chromosomes in amles and females. In Drosophila, by contrast, dosage compensation is acheived by increasing the level of expression on the male X chromsome. 

The X chromosome inactviation mechanism of dosage compensation is true of all mammals. Females that are heterozygous for X chromosome alleles are egentic mosaics in that their individual cells may express different alleles, depending on which chromosome is inactivated. An example is the calico cat, a female that has a patchy distribution of dark fur, orange fur and white fur. The dark and orange fur are due to heterozygosity for a gene on the X chromosome that determines pigment color. One allele results in dark fur, and another allele results in orange fur. Which of these colors is observed in any particular patch is due to inactivaiton of one x chromsome. If the chromosome containing the orange allele is inactivated, then the fur will be dark and vice versa. In addition, the patchy distribution of colr and the rpesence of white fur is due to a second gene that is epistatic to the fur color gene. The presence of this second gene produces a patchy distribution of pigment, which some areas totally lacking pigment. In the areas that lack pigment, the effect of either fur color allele is masked. Thus the caolico cat is an exaple of both epistasis and X inactivation. 

Aneuploidies:

The particular array of chromosomes an individual organism possesses is called its Karyotype. In the human karyotype, the 23 pairs of chromosomes differ widely in size and in centromere position. 

The failure of homologues or sister chromatids to separate properly during meiosis is called nondisjunction. This failure leads to the gain or loss of a chromosome, a condition called aneuploidy. The frequency of aneuploidy in humans has been estimated at 7010% of clincially recognized conceptions. Inidivduals who have lost one copy of an autosome are said to be monosomic, and generally do not survive embryonic development. In all but a few cases, individuals who have gained an extra autosome (called trisomics) also do not survive. Data from linically recognized spontaneous abortions indicate levels of aneuploidy as high as 35%. 

Embryos trisomic for 5 of the smallest human autosomes (numbers 13, 15, 18, 21 and 22) can develop and survive to live . Trisomy for 13, 15 or 18 casues severe developmenal defects and infants with such a genetic makeup die within a few months. In constrast, individuals trisomic for chromosome 21 or mroe rarely #22, usually survive to adjultood. In these individuals, the matruation of the skeletal system is delayed, so they generally are short and have poor muslce tone. Their mental devleopment is also affected, and children with trisomy 21 show dome degree of intellectual disability. 

Aneuploidy:

The presence of a variation in the number of chromosomes from the usual complement of 46 is referred to as aneuploidy. The absence of a single chromosome from a usual pair is referred to as monosomy, and presence of an additional copy of a single chromosome to the usual pair is referred to as trisomy.

Aneuploidy refers to the state where the wrong number of chromosomes (e.g., the wrong number of full chromosomes or the wrong number of chromosome segments, such as presence of deletions or duplications of a chromosome segment) is present in a cell. In the case of a somatic human cell it may refer to the case where a cell does not contain 22 pairs of autosomal chromosomes and one pair of sex chromosomes. in the case of a human gamete, it may refer to the case where a cell does not contain one of each of the 23 chromosomes. In the case of a single chromosome tyype, it may refer to the case where more or less than two homologous but non-identical chromosome copies are present, or where there are two chromosome copies present that originate from the same parent.  (Natera, US 10,262,755)

Nondisjunction of sex-chromosomes:

Aneuploidy for the sex chromosomes has less severe consequences than autosomal aneuploidy. Nondisjunction of sex chromosomes can occur in either male or female meiosis. In fmale meiosis, this will produce oocytes with either two X chromosmes, or no X chromosome. In male meiosis, the cutcome depends on whether the nondisjunction occurs during meiosis I or II, and can produce XY sperm, YY sperm and sperm with no sex chromosomes. Variousombinations of these gametes and normal gametes leads to zygotes with sex chromosome aneuploidies: XXX, XXY, XO, OY and YYY. The most extreme case is the complete lack of an X chromosome (OY), which resutls in embryonic lethality. At the other end of the spectrum, XXX individuals develop into females with one funcitonal X chromosome. They may be taller in stature, but are otherwise indistinguishable from XX females. An XXXY individual develops as a male with many female body characteristics and in some, but not all cases, diminished mental capcity. This condition, called Klinefelter syndrome, occurs in about 1-1000 male births. 

Copy number variation (CNVs) are often assigned to one of two main categoreis, based on the lengh of the affected sequence. The first category include copy number polymorphisms (CNPs) which are commin in the general population, occurring with an overall frequency of greater than 1%. CNPs are tpically small (most are less than 10 kilbases in lengh) and they are often enriched for genes that encode proteins important in drug detoxification and immunity. A subset of the CNPs is highly variable with respect to copy number. As a result, different human chromosomes can have a wide range of copy number (e.g., 2-5) for a particular set of genes. CNPs associated with immune response genes have recently been associated with susceptibility to complex genetic diseases, including psoriasis, Crohn’s diease and glomerulonephritis. The seocnd class of CNV include realtively rare varints that are much longer than CNPs, ranging in size form hundreds of thousands of base pairs to over 1 million base pairs in lenght. In some cases, these CNVs may have arisen druing production of the sperm or egg that gave rise to an individual or they may have been passed down fro only a few generations. (Natera, US 10,262,755)

Gene copy number and Diseases:

Gene copy number can also be altered in cancer cells. For instance, dupolicaiton of Chrlp is common in breast cancer and the EGFR copy number can be higher than normal in non-small cell lung cancer. (Natera, US 10,262,755)

A higher copy number of CCL3L1 has been associated with lower susceptibility to HIV infection, and a low copy nmber of FCGR3B (the CD16 cell surface immuoglobulin receptor) can increase susceptibility to systemic lupus erythematosus and similar inflammatory autoimmune disorders. (Natera, US 10,262,755)

Aneuloides in autosomal and sex chromosomes are responsible for a number of genetic conditions including Down syndrom (trisomy of chromosome 21), Edwards syndrome (trisomy of chromosomes 18), Patau syndrome (trisomy of chromosome 13)., Turner syndrome (full or partial monosomy of X), Klinefeiter syndrom (XXY), XYY syndrome, XXYY syndrome and Triple X syndrome. 

The most commo viable autosomal trisomies are trisomies of chromosomes 21, 18 and 13. Trisomy 13 and trisomy 18 often result in miscarriage, stillbirth or in the case of viable birth, neonatal death. Trisomy 21 is not usually life threatening but can result in significant physical and mental disability. Fetuses with aneuploidies of multiple chromosomes are unlikely to survive past the early stages of pregnancy. The additional chromosomes found in cases of trisomy may be paternally or maternally inherited. In trisomies 13, 18 and 21, the extra copy of the relevant chromosomes is inherited form the mother in the majority of cases. 

Detection of Deletions and Duplications of chromosome segments or entire chromosomes:

(Natera, US 10,262,755) disclsoes determing whether an aneuploidy mutation is present by analyzing a sample of blood to dtermine a level of allelic imblance fourality of chromosomes or chromosome segments known to exhibit aneuploidy in cancer by generating nucleic acid sequence data for a set of polymorphic loci on each of the plurality of chromosomes or chromosome segments, using the nucleic acid sequence date to generate phased allelic data fot teh set of polymorphic loci on each of the pourality of chromosomes or chromosome segmetns and termeing the level of allelic imbalance prsent for each of the plurality of chromosomes or segments using the phased allelic data, wherein a detectable allelic imbalance is indicative of an aneuploidy mutation in the solid tumor for each of the plurality of chromosomal segments. Allelic data refers to a set of genotypic data concerning a set of one or more alleles. It can refer to the phased, haplotypic data. it may also refer to SNP identities and it may refer to the sequence data of teh DNA, including insertions, deletions, repeats and mutations.