Non-Mendelian Inheritance
Gregor Mendel was fortunate to have chosen some of the most genetically simple of characters in the garden pea for his seminal experiments that laid the foundation for the science of genetics. Each was determined by a single gene on a different chromosome, and each trait behaved as clearly dominant or recessive in this experimental system. This allowed Mendel to recognize patterns of heredity, which are described as the law of segregation of alleles, and the law of independent assortment. In its broadest sense, non-Mendelian inheritance includes any hereditary phenomena that do not appear to conform to Mendel's laws or to be attributable to single autosomal genes. It is not a clearly-defined classification, and is used quite variably in the scientific literature.
Arguably, the first form of non-Mendelian inheritance to be recognized was sex-linked, since Mendel studied only autosomal characters; however, this is rarely cited as such. Also, genes that are closely linked on the chromosome will tend to assort together rather than independently, but this too can be understood as part of classical inheritance.
Complex or multifactorial traits are determined by multiple genes and environmental factors, and therefore do not conform to simple Mendelian patterns. The human single-gene Mendelian disorders (such as those catalogued in McKusick's Mendelian Inheritance in Man) typically are individually rare, whereas the complex non-Mendelian disorders include more common afflictions such as heart disease, cancer, diabetes, psychiatric disorders, and many others that are becoming more experimentally accessible with recent advances in genomics.
Even with single-gene traits, various factors can alter the regularity of transmission and expression. The same genetic trait may be expressed differently in different individuals (variable expressivity), or not at all as in the case of non-penetrance.
Anticipation refers to the progressively earlier appearance and increased severity of a disease in successive generations. Many such examples can now be explained by the phenomenon of dynamic mutations caused by expanded trinucleotide repeat regions. Superimposed upon these are parent-of-origin effects that make expansion in gametes of either females or males more likely.
Mendelian traits are determined by nuclear genes, but organelles such as chloroplasts (in plants) and mitochondria also have DNA containing genes, with their own inheritance characteristics. This form of non-Mendelian inheritance is called extranuclear, cytoplasmic, or maternal inheritance. The latter is due to the fact that sperm do not contribute to the cytoplasm of the zygote, and therefore all mitochondrial genes are maternally derived. The inheritance of traits from mitochondrial genes is therefore always from mother to offspring.
Situations in which the parental nuclear alleles are not represented equivalently in the offspring defy Mendel's Law of Segregation, and are variously called transmission bias, segregation distortion, or meiotic drive. The t-locus in mouse, segregation distorter in Drosophilae and retinoblastoma locus in human provide examples, with various underlying biological explanations, in which mutant alleles are differentially represented in offspring, with parent-of-origin effects.
The extreme in transmission bias is uniparental inheritance, in which only one parental genotype (for a given locus) is represented in the offspring. This can be caused by errors in chromosome segregation that result in two alleles being derived from one parent and none from the other. Rare cases of cystic fibrosis in which only one parent is a carrier can be explained by this non-Mendelian phenomenon. It is also an anomaly that creates problems for genes that are normally imprinted.
Epigenetic inheritance involves genetic changes other than changes in DNA sequence. The best understood mechanism for such change is DNA methylation, and the relevant phenomenon is imprinting. Although certain genes themselves may be inherited in a Mendelian fashion, their expression is over-ridden by the epigenetic factors to influence expression of the genes. At the level of the traits being studied, then, there is a difference between two types of crosses with respect to the sex of the parent transmitting a particular gene, and the outcome in the progeny. Classic examples include the insulin-like growth factor 2 (Igf2) gene in mouse, and the Prader-Willi / Angelman region in human.
These ever-increasing exceptions to the rules of Mendelian inheritance, once deemed heretical or inconsistent with genetic transmission of any kind, are now the basis for some of the most intriguing and informative of genetics research.
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