In the evolution and heredity of human diseases, there have been multiple theories proposed to explain how extremely

deleterious diseases persist in the human population at varying levels. An early theory, was the idea of common disease, common variant. This theory proposed that very common diseases, such as heart disease, are all caused by one, or a few, common alleles. This idea was very appealing, because if there were only a few genes causing really serious and really common diseases, then targeted drugs could be designed to treat the underlying genetic causes of diseases. However, many years of research showed that this theory for genetic inheritance of disease is not supported by genome wide association studies. In the wake of these results, there are two major theories that have been proposed to replace common disease, common variant. The infinitesimal model argues that diseases are caused by an enormous number of genes that all play a small role creating the phenotype. Under this model, genome wide association studies have not found any causal genes in diseases because the contributions are too small to be detected. The infinitesimal model does have some evidencein common phenotypes. Height is an example of a trait that seems relatively simple, but it caused by hundreds, if not thousands of genes. Even with the several hundred genes that have found to contribute, only a small percentage of inheritance is still explained. Through this model, it also seems logical that really deleterious diseases could persist at high rates in the human population. Because of independent assortment, slightly deleterious alleles would persist, and only cause diseases when in a combination of many hundreds of alleles, that also make very tiny contributions. Despite how applicable the infinitesimal model seems, the major downside of it, is that it has never been observed and quantified in human diseases. This is partly a

technological problem, in that tests are not exact enough to confirm this theory. This is also a problem because pedigrees, a traditional way of mapping heritability would not help explain the infinitesimal model. Heritability studies assume that an allele is rare enough, that you can predict who in the family will have it, based on inheritance patterns. But if all of the alleles that cause diseases are very common, and it is simply a matter of whether you have the right combination in the right quantity, then the inheritance of things like heart disease seems almost random almost anyone could be at risk. The other possibility for the causes of disease, is the rare allele hypothesis. Under the rare allele hypothesis, there are many different, extremely rare alleles that all lead to the same diseases. These alleles are almost entirely exclusive to family pedigrees, and each family which has the same phenotypic disease, is actually caused by different alleles. These new mutations are unique, and they are heritable within the family pedigree. This theory is strongly supported by some experimental evidence. According to the rare allele hypothesis, these extremely deleterious alleles are incredibly rare, which is consistent with evolutionary theory. The evolutionary argument is that deleterious mutations should be rare because they inhibit reproduction, and are strongly selected against. However, due to high mutation rates, and the size of the human population, deleterious mutations do occur, and do get passed on through generations. Further, population genetics has confirmed that severely deleterious mutations are rare in the populationwhich is more experimental evidence than can support the infinitesimal argument. In the rare allele model, the causes of disease are a small number of alleles that have an enormous effect (usually with high penetrance), and this is supported by genetic data about cystic fibrosis, and muscular dystrophy, among

many other disorders. There is substantial evidence for rare allele mutations, while the evidence for the infinitesimal model is scarce. Even brain diseases, which are extremely difficult and complicated to explain, have been shown to be partially caused by a small number of alleles that have large effects. Although diseases such as autism and schizophrenia are not caused by one or two strong alleles, the greatest contributions do come from only a few, and the environmental factors likely play a large role. The downsides of this argument, is that it makes large, population studies really difficult. If every family has a different allele that causes heart disease, then learning about the causes of heart disease in family A, is not particularly helpful to the general population. Further, genome wide arrays have not supported this genetic theory of inheritance patternsrare alleles of high affect are severely underrepresented. Another criticism of this theory, is that there are high sibling reoccurrence rates of disease, which are much higher than this model would predict. However, this criticism might not be entirely valid because although rare alleles have high effects, there can be some combination of low contribution alleles, as well as environmental factors, which cause complicated diseases. Comparing the arguments for the rare allele hypothesis and the infinitesimal model, there is a great deal more evidence in support of the rare allele hypothesis. There are multiple diseases which have been confirmed to follow the rare allele hypothesis, while the most prominent example of the infinitesimal model is height, which is a trait rather than a disease. There are diseases relating to height, like dwarfism, but they are generally caused by rare alleles of enormous effect, rather than a huge number of small affect alleles.