11.3 The genome – more complex than the sum of its genes


Every human being has a unique genome with variations in an enormously large number of gene loci and this means nothing else than all human beings differ from each other in a huge number of individual bases on their chromosomes. One also terms such punctual differences of the base sequence "SNPs" or "single nucleotide polymorphism". How SNPs and diseases are connected has still been too rarely investigated.

If a genetically determined characteristic does not fit in with the simple Mendel's inheritance laws and, in addition, is variably expressed, one can assume that either several genes take part in the expression of the characteristic (--> polygeny) or a genetic disposition is present that, in an interplay with partially unknown factors, is also responsible for it (--> multifactorial inheritance).
If it is only environmental factors that have influence on the phenotype in the same genotype, one speaks of flowing modifications.
Fig. 18 - Complex inheritance pattern  Legend

In this family tree no simple Mendel's Law conformity in the inheritance pattern is evident. A complex inheritance pattern is present in which the genetic variations alone are not able to explain the illness.

Furthermore it must be taken into account that some diseases and abnormalities do not occur equally frequently or with the same intensity in both sexes. Probably the genetic disposition or genomic imprinting plays an important role thereby.

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Genomic imprinting

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A phenomenon that has been known for thousands of years can probably be explained with the differing genomic imprinting of the two parental genomes. Via the crossing of horse and donkey, one obtains two kinds of offspring with differing appearance and differing characters.

  • Mules when the mother was a female horse and the father a male donkey.
  • Hinny when the mother was a female donkey and the father a male horse.

Both the mule and the hinny are not able to reproduce.

SNPs or single nucleotide polymorphism

Not every mutation of the base sequence means a pathogenic alteration of the genome. There are the single nucleotide polymorphisms (SNPs) or single letter variations in the DNA sequence. Today SNP maps exist in which all currently known polymorphisms are stored and are available for scientists to use (13). One knows between 1.42 and 2.1 million SNPs. They occur on average with a frequency of 1 SNP per 1910 bases with regional differences. The least SNPs happen to the X chromosome and, in general, SNPs occur more often in the intron DNA segments as in the exon segments that contain information regarding the AS sequence of the proteins. The SNPs represent very individual information with whose help, today, the genetic "fingerprinting" for paternity cases or in forensics are performed.

A more exact study of SNPs is also very interesting from the point of view of diseases that are complex and are probably based on combined changes to various genes (polygeny).
Combinations of SNPs are known that make certain diseases more likely or, in the best case, improve resistance to certain illnesses.
Fig. 19 - Example of an SNP with
phenotypical consequences

Fig. 19
Here two identical chromosome segments (SH2D1A gene of the X chromosome) of two individuals (A and B) are compared. One SNP is shown as a variation in a base pair. In individual B cytosine (C) has been replaced by thymine (T) (pink). This "single nucleotide"exchange leads to a predisposition for an uncontrolled overproduction of B and T cells after an infection with an Epstein-Barr virus (Burkitt's lymphoma).

Polygenic and multifactorial hereditary disease

Today one knows diseases that are caused by the combined effects of various genes. Such illnesses are most often due to polygeny or multifactorial inheritance. If a predisposition (due to genetic and environmental factors) is known, prophylactic measures can possibly be undertaken against it. The search for underlying, predisposing genetic variations as well as the number and kind of the environmental factors that are involved is very difficult, however, since such diseases do not obey the simple mendelian laws. .

The following example should show a disease that, on the one hand, is caused polygenically and, on the other hand, is influenced by environmental factors. In epidemiological studies the incidence for gene variants that are responsible for this disease were determined in a population of patients with this illness. Fig. 20 - Multifactorial causes for a disease  Legend

Fig. 20
The figure shows that besides the genetic predisposition still further factors (environment / lifestyle) have an influence on causing an illness to break out. Further, it becomes clear that even if variants of the A gene appear to make having the illness very likely, they nevertheless do not suffice to explain it.

In examining individual families that have been affected, it can happen that distribution patterns of the various gene variants are found that are totally different than in the general population (compare the multifactorial inheritance figure). This shows that in many complex diseases predisposing polygenic factors must indeed be present. These factors alone are not enough, though, to explain the disease or abnormality sufficiently well. In individual families environmental factors and differences in lifestyle must also be involved that cannot be known in detail.

Fig. 21 - Analysis of the gene variants in four different families  Legend

Fig. 21
In one family (no. 3) a rare gene variant C may have a large influence on the predisposition for having a disease although this gene variant has only little influence in the general population.

Finally, one must mention that the proportion of the genes and environmental factors change in how they influence a symptom and this can only be investigated through twin and adoption studies. It is indeed true that the genes that are involved are inherited in accordance with Mendel's laws, but how the symptoms are expressed and the appearance of the disease/abnormality is the sum of the individual genes. This is also termed an additive gene effect. In certain symptoms, though, the additive gene effect for their expression must exceed a threshold, whereby the individual gene variations correspond to the normal distribution in the general population. One also calls such mutual influencing of two genes with different gene locations epistasis.

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Examples of multifactorially conditioned hereditary illnesses:

  • Asthma
  • Congenital pyloric stenosis
  • Congenital hip displacement, clubfoot
  • Cleft lips-jaw-palate (3)
  • Congenital cardiac defect
  • Coronary cardiac diseases
  • Bifid spine
  • Schizophrenia
  • Affective psychosis
  • Type 1 diabetes

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