Box Alleles

Mendelian inheritance is concerned with the transfer of genetic information from parents to children. The alternate forms of the same gene are known as alleles. When an individual has two identical alleles, they are described as homozygous, when the alleles differ, as heterozygous. A child receives one allele from each of their parents for a given autosomal gene. If there is a genetic difference between the alleles, having one 'normal' allele (often denoted 'A') and one 'variant' allele ('a') may be sufficient for a particular phenotype or trait to become manifest. The individual is heterozygous for the alleles ('Aa'), and inheritance of the character (also described as the trait or phenotype) is described as autosomal dominant. One copy of the variant allele is sufficient, for example, to result in disease, as seen in Huntington's disease where an unstable repeat expansion in the DNA sequence causes a dramatic change in the encoded protein which is toxic to the cell (Box 7.13). Sometimes the character will only be manifest if an individual inherits two alleles with the variant (homozygous 'aa'). The phenotype is described as autosomal recessive and examples include cystic fibrosis (Section 2.3.1).

individuals are homozygous for this allele (Box 1.8). By contrast, possession of one chromosome with the variant encoding Hb S while having a second normal chromosome which continues to encode adult haemoglobin, Hb A, results in sickle cell trait ('Hb AS'). This has minimal adverse effect except under conditions of more severe hypoxia such as underwater diving or high altitude. In most conditions therefore, heterozygous individuals with sickle cell trait are phenotypically normal and the inheritance of sickle cell disease can be described as autosomal recessive. However as heterozygotes will express Hb S as well as Hb A, when the altered form of haemoglobin is considered as the observed phenotype, it is inherited as a co-dominant trait.

This illustrates how the mode of inheritance refers to the specific trait or phenotype under consideration. Thus the presence of a single copy of an allele with the sickle variant can also be considered co-dominant in terms of susceptibility to sickling at high altitude, or overdominant in terms of conferring the phenotype of resistance to malaria. Here heterozygotes (those with sickle cell trait) have a marked advantage in terms of protection from malarial infection due to Plasmodium falciparum without the cost of sickling crises and other pathology seen in homozygotes with sickle cell disease (Allison 1964). This selective advantage is thought to have been responsible for the relatively high allele frequency of the genetic variant responsible for sickle haemoglobin in sub-Saha-ran Africa and parts of India (Section 13.2.3).

It has also become apparent that sickle cell disease can arise if an individual has a copy of the Hb S variant together with some other sequence variant involving the HBB gene (such as resulting in Hb C) (Section 1.3.1). It was also notable that among patients homozygous for Hb S there is clinical heterogeneity in the severity of the disease phenotype observed, ranging from early death to disease with few complications. Genetic modifiers include a-thalassemia and variants determining the levels of Hb F. The latter were known to include rare deletions in the p globin gene cluster and point mutations in y-globin genes resulting in hereditary persistence of fetal haemoglobin, but more recent work has identified variants near HBB and in other chromosomal regions which together are associated with determining nearly half of the variance in levels of Hb F among non-anaemic populations (Higgs and Wood 2008a). The functional mechanisms remain unclear but the variants on chromosome 2 and chromosome 6 may involve the oncogene BCL11A and haemopoietic transcription factor MYB respectively.

For multifactorial traits and diseases (sometimes described as 'complex' or 'polygenic diseases') such as malaria (Box 13.1) or rheumatoid arthritis (Section 12.2.3), genetic factors play a role but are not inherited in a simple mendelian manner. Here, multiple genetic loci and variants are important in determining disease susceptibility together with environmental factors. The lines of division between such diseases and classical 'mendelian' disorders are however becoming increasingly blurred. Indeed, the growing awareness of the complexity of the genetic and other determinants of sickle cell disease have promoted the proposal that rather than considering this disease as a simple monogenic condition it should be 'considered as a complex multigenic disorder' (Higgs and Wood 2008a).

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