32 Genetics and Human Health

Amitabh Biswas

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CONTENTS

 

1.  Learning Outcomes

 

2.  Introduction

 

3.  Genetics – Basic Understandings

 

4.  Monogenic Disorders

 

5.  Polygenic Disorders and Haplotyping

 

6.  Multifactorial Disease and Environmental Factors

 

7.  Disease or Protective Trait

 

8.  Issues in Genetics and Health

 

1. Learning Outcome

 

After Studying This Module:

  • You shall be able to understand the importance of genetics in health, whether monogenic or complex disease, role of genes and genetic variations to modify the status of disease.
  • You would be able to understand advantages of alterations in genome in human health and also how other factors such as environment; behaviour etc. can modify the genetic effect.
  • You would know, how a genetic status could be deleterious in one population but advantageous in other condition in different population.

 

2.  Introduction

 

This study module deals with a very important prospect of life– our genes, which is a region where there is lots of human diseases domain as per medical aspects. We will have a look for t he inheritance patterns, gene function and inter and intra differences between people and populations.

 

3. Genetics – Basic Understanding

 

Genetics basically deals with the genetic components and traits passes to offspring’s to parents. These traits can be height, skin or hair color as well as complex disease susceptibilities. When we combine both clinical phenotype and a basic science, issues related to medical genetics can be addressed. It makes us understand the function of health and disease in the human. Overall, advancement in technologies created opportunities to understand, prevent, treat and provide therapeutic interventions for the human diseases.

 

For the Breast cancer, It is now frequent in reporting about the presence of BRCA1 and BRAC2 gene to be used as causative part and directly linked to the condition and called to have the disease. This is highly misunderstood: each person has the BRCA1 and BRCA2 genes, for their functional work, i.e. In breast and ovarian cancer the tumour growth is suppressed. Breast Cancer risk is due to inheritance of mutated allele, either from father or mother which removes that protective shield which suppresses tumour growth (Narod & Salmena, 2011).

 

Conventionally, single gene single disorder was pronounced which means diseases which are caused by mutation in single genes such as cystic fibrosis or Huntington disease, etc. Yet, at present there is a paradigm switch from individual genes to multiple genes (genomics) and their gene- gene interactions as well as gene-environment interactions (epigenetics).

 

Our apprehension of complex genetic disorders such as malignant neoplastic disease and diabetes has been increasing due to technology advancement, these diseases are influenced by a number of risk factors including environment stimuli. This has resulted in a more mainstream approach to the application of genetics and genomics to a broad diversity of clinical problems in the health care context. Ridley has pointed out that the tendency to identify a specific gene as the cause of disease obscures the critical function of genes in human wellness. It is also noted that genetic disorders like beta thalassemia are inherited in autosomal recessive pa ttern can be checked and removed from the population because both disease allele are required to causes disease. Carrier marrying carrier may have offspring with both disease allele which would lead to disease (Fig 1).

 

In human genome Catalogues, list of diseases named after the doctor who identified, but the genes are yet to be identified. The diseases caused by gene don’t define the genes, it’s like defining body organs by diseases: hearts to cause heart attacks, cirrhosis caused by the livers, and kidneys to cause renal failure. But the cataloguing is done is similar fashion which may mislead. It is true that for most of the genes, we know about the malfunction causing diseases and this is a very small piece of information about genes. An individual has Wolf-Hirschhorn gene doesn’t mean that he/she might get the disease which is incorrect information. Subjects who had Wolf-Hirschhorn syndrome doesn’t have Wolf-Hirschhorn gene, but all other individuals have. There disease condition is because of missing of particular gene but it is present in all other normal individuals. It implies that disease person had a mutation in particular gene not just had a gene (Ridley, 1999).

 

Classification of genetic disorders is done in a number of ways (Trent, 1997). For the topic, undertaken, it can be best classified as:

  • Monogenic (or single gene) disorders;
  • Polygenic (or multi-gene) disorders; and
  • Multifactorial disorders.

 

In addition, there are chromosomal disorders (such as Down syndrome) (Cohn, 2003) and somatic cell disorders (such as cancer), in which the genetic abnormality was not present at conception but was acquired during life and is found only in specific cells rather than in all cells in the body (Frank, 2009).

 

Table 1 below lists a number of more common genetic disorders. The table list of common genetic diseases, and chromosomes.

(http://www.meddean.luc.edu/lumen/MedEd/USMLE/Table_of_Genetic_Disorders.pdf).

 

Table 1. List of the common genetic disorders with chromosome number

  1. Monogenic disorders

 

When a mutation in one or both alleles of a single gene is the causing factor in a genetic disorder is known as monogenic disorders. Studies on Monogenetic disorders like Huntington’s disease (HD), made us realize the impact of genetics in human health, disease, HD is a relatively rare disease but is caused by genetic abnormalities. The Huntington’s disease is end phenotype of genetics. The changes in environmental aspects like healthier lifestyles, medicine can modify your lifestyle disease like diabetes, obesity, but pure genetic disorders like beta thalassemia, HD are inevitable and can’t be reversed if you had genetic abnormalities for the disease. Your genes decide your future (Ridley, 1999).

 

The rarity of monogenic disorders is an important consideration in developing a policy framework for the protection of human genetic samples and information. Monogenic disorders allow relatively accurate inferences to be drawn about a person’s future health from their current genetic status. However, this is not the case with the vast majority of genetic disorders, where the relationship between genetic status and disease is highly complex and contingent.

 

Figure 2. Graphical Representation of monogenic and complex disorders (Source- http://www.dialogues-cns.com/publication/a-glossary-of-relevant-genetic-terms/).

 

5. Polygenic disorders and haplotyping

 

The vast majority of medical conditions with genetic perspective involve either the interaction of a number of genes (polygenic) or the interaction between genes and the environment (multifactorial disorders) which is very complex to understand fully (Trent, 1997a).

 

As Ridley has stated:

 

“Unless you are unlucky enough to have a rare and serious genetic condition, and most of us do not, the impact of genes upon our lives is a gradual, partial, blended sort of thing. You are not tall or a dwarf, like Mendel’s pea plants, you are somewhere in between. You are not wrinkled or smooth, but somewhere in between. This comes as no great surprise, because just as we know it is unhelpful to think of water as a lot of little billiard balls called atoms, so it is unhelpful to think of our bodies as the products of single, discrete genes.”(Ridley, 1999a)

 

Total of 14,014 genes have been mapped and reported to individual chromosomes and out of which 1,639 genes are associated with genetic disorders as suggested in Human Genome Database, published in 2002 (Kent et al. , 2002). The rate of discovery has slowed dramatically regardless of better technology on the mark; it may be that most of the simple linkages have already been made. Only 17 genes were identified with a genetic disorder out of the last 3,783 genes which had mapped.

 

According to Dr. Francis Collins, Director, United States “National Human Genome Research Institute” (NHGRI) after success of the “Human Genome Project”, the ‘next huge thing’ is to produce a Human Haplotype Map. A number of closely-linked alleles along a region of a chromosome, which tend to be inherited together, are referred as Haplotypes (or haplotype blocks) (www.nhgri.gov, International HapMap Consortium)

 

According to NHGRI:

 

“The elucidation of the entire human genome has made possible our current effort to develop a haplotype map of the genome. The haplotype map, or ‘HapMap’, will be a reference work that catalogs the genetic variations of most importance to health and disease.”

 

All individuals have 99.9% identical DNA sequences. Individual’s disease risk may be greatly affected by the variations inherited/occurred. Single base differences in the DNA sequence where individuals differ are called single nucleotide polymorphisms (SNPs). Group of SNPs in close proximity on the same chromosome are inherited in blocks. The pattern derived from SNPs group is considered as haplotype. There could be large number of SNPs in the blocks but a relatively few SNPs are enough to uniquely identify a haplotype. Mapping of these haplotyping blocks including the specific SNPs that identifies blocks is known as HapMap.

Individuals at risk for particular diseases could be identified by comparing the patients genetic pattern with the known patterns form HapMap, it will help researchers to locate the diseases associated blocks or genes. The HapMap will enable researchers to examine drug efficacy to provide specific treatment because people with the same disease may respond differently to the same drug treatments. Finally, haplotype mapping will disclose the role of disparity in individual responses to environmental factors.

 

Recent research reveals that there are a smaller number of common haplotypes, although theoritically, in a chromosome region, there could be large numbers of haplotypes. There are four or five common patterns across all populations which would make researchers to minimize their experiments by testing for genetic predispositions block-by-block not by letter by letter for such complex diseases as cancer, diabetes, hypertension, and Alzheimer’s (Gabriel et al., 2002).

 

‘Common variant hypothesis’ proposed by researchers have made three important points:

 

First, the human genome can be objectively divided into straightforward haplotype blocks each ranging 11,000 to 22,000 DNA letters, but only four or five different variations in the letters. Second, the haplotypes blocks are comparable across individuals from Asia, Africa, and, Europe indicates that HapMap will have broad effectiveness for most people. Third, 90 percent of genetic variation in a region of the human genome was able to be captured by the haplotype blocks (Morton, 2002).

 

This type of study is an important step toward developing a more powerful statistical approach to study complex human disease. In complex disease, genetics could not able to understand the mechanism biology, even though great effort has been put in during the last 10 to 15 years. From our efforts, we’ve come to comprehend that complex diseases are not caused by a single high-penetrance genes, but from more unpretentious risk factors common in populations as per Mark Daly’s one of the authors. This study provides an opportunity for scientists to treat and improve models of population biology and molecular evolution. For Initial for population, genetics workout easy, but for a disease, it’s a comprehensive and difficult task to handle (Morton, 2002).

 

  1. Multifactorial Disease and Environmental factors

 

Multifactorial disorders means not only mutation inherited will make individual vulnerable or predisposed to develop the condition but there are other risk factors such as unbalanced diet or stress or exposure to some environmental factors which are involved to contribute in the expression of the disorder. Common health problems in humans such as heart disease, hypertension, psychiatric illness (such as schizophrenia), dementia, diabetes, cancers etc. are multifactorial.

 

For a decade, the prevailing convention was that “Nurture (environment) is more important than Nature (genes)” in course of human health development (Rose et al., 1984). The rate and burden of genetic research in recent times, however, have been in other direction prior to convention—perhaps too far in the direction of genetic exceptionalism and determinism. In fact, the depiction is far more compound. An individual is not the addition of a column of traits and behaviors resulted by individual genes. As an alternative, it was proposed that Individual have the total product of genes; the complex interaction of those genes; and the comprehensive interaction between that genetics and environmental factors is present.

 

Even a straightforward situation to ‘the environment’ minimizes the dynamic and widespread nature of this relationship. If we had a look for environment quality- a balanced and hygienic diet, Good health care access, Exercise – will allow the entire expression of genetically inherited traits, such as height. Over a time span, other features of the physical environment also will modify human health and development – like air and water pollution, endemic disease, drought and war etc. Choice and chance also play a significant role – smoking and skydiving create dangers to health unrelated to genetic inheritance, and a high speed, head-on car accident will always trump good genes.

 

It is well said:

 

“You had better get used to such indeterminacy. The more we delve into the genome the less fatalistic, it will seem. Grey indeterminacy, variable causality and vague predisposition are the hallmarks of the system … because simplicity piled upon simplicity creates complexity. The genome is as complicated and indete rminate as ordinary life, because it is ordinary life. This should come as a relief. Simple determinism, whether of the genetic or environmental kind, is a depressing prospect for those with a fondness for free will.” (Ridley, 1999b)

 

The environment is also occupied of social entities that have an effect on our health and the chances to acquire our complete potential. For example, if a women is restricted to receive higher education or if community through discrimination blocks certain racial groups from any employment, then utilization of essential intellectual ability will be minimum.

 

7. Disease or protective trait?

 

Genetic variations or mutations are commonly presented as ‘diseases’ or ‘disorders’ but in the past, some of these mutations considered to enhance the prospects of survival in some environmental contexts. Some examples in which the genetic ‘abnormality’ does not cause any disease condition for carrier (inherited affected mutation from single parent) involve autosomal recessive conditions but would result in disease condition if a child who had both inherited genes affected from both parents (Trent, 1997).

 

7a. Beta-thalassemia is common blood disorder in the Mediterranean region and in several parts of Southeast Asia. The genetic abnormalities in beta-globin gene causes disruption in the synthesis of a Beta-globin protein which are found in RBCs. Carriers (who have only one allele is mutated) are expected to have mild anemia (doesn’t cause any serious health problems) but the both allele affected person has severe anemia, which usually requires life-long blood transfusion. Whereas the carrier state, found in as many as 1 in 10 people in some populations, gets protected against malaria because RBCs of carrier’s individuals are small and pale which doesn’t make available a good environment for malaria parasite in which they can grow (Galanello and Origa, 2010; Rund et al., 1991).

 

7b. Tay–Sachs disease (TSD) – It is common in the Central and eastern European (basically in Ashkenazi Jewish community) than from Middle Eastern (Non-Jews or Sephardic Jews), with carrier frequency of approx. 1 in 30. Tay-sachs disease is a neurological degenerative disease which results in deaths in 4-5yrs of age. Similar to beta thalassemia, there is no symptoms of the disease for TSD Carriers, but it had been observed that the carrier state had protection against tuberculosis (TB) for the Jewish population who lived in the restricted conditions of the ghettos for the times past (Spyropoulos et al., 1981; Arpaia et al., 1988).

 

7c. Cystic fibrosis (CF) is common among Caucasians with a prevalence of 1 in 25 of whom are carriers for CF also found in numerous ethnic groups. The Chloride movements gets affected and found across the cells and causes lunges and pancreas problems in disease state (Riordan et al., 1989). Carriers for CF do chloride (i.e. salt) movement wasn’t found across their membranes similar to those of non-carriers, and are at reduced risk of mortality from diarrhoea. When cholera and dysentery were endemic, carrier of this mutation may become beneficial over the many thousands of years of evolution. Carriers commonly don’t have the symptoms of CF, therefore carrier status can found through DNA screening but inheritance of the CF mutated allele from both parents may lead to severe health problems (although CF is heterogenous in terms of severity) (Verkman et al. , 2006).

 

7d. Sickle cell anaemia is common genetic disorder among individuals from Africa and the Mediterranean area. It is caused by a mutation in the haemoglobin gene (Stuart et al., 1981). The carrier state affords protection against malaria, however, because carriers have abnormal red blood cells that die soon after being infected with the malaria parasite, compared with normal red blood cells, which continue to work and to provide an environment in which the malaria parasite can grow. In an evolutionary sense, being a carrier for sickle cell disease is a good thing if one lives in a region in which there is endemic malaria (Luzzatto, 2012).

 

The link between an individual’s genetic status and the expression of a genetic disorder, and the link between the expression of a disorder and particular health outcomes a need to be understood to address disease status and therapeutic interventions. In particular, there are difficulties in interpreting genetic information in a way that is reliable and relevant for the many contexts in which genetic information is or may be used, now and in the future.

 

8. Issues in Genetics and Health

 

Recent times, Genomic research may significantly change the practice of health care and management. But only genomic research is not sufficient to relate this upcoming field to improve human health. We need to carefully understand all ethical, legal and social issues raised by this type of research. Such study is vital to being able to use genomic research to help patients and preventing misuse of new genetic technologies and information available. Issues raised by genomic research include: Ethical standards required to work on human subjects or tissues, possible discrimination by employers and health insurers and consideration of social, cultural and religious perspectives of genetics and health. There is a need of proper regulation of genetic testing and privacy of patients should always be maintained to avoid any discrimination (WHO, 1997).

 

Summary

  • Genetics basically deals with the genetic components and traits passes to offspr ing’s to parents. These traits can be height, skin or hair colour as well as complex disease susceptibilities.
  • When we combine both clinical phenotype and a basic science, issues related to medical genetics can be addressed
  • Conventionally, single gene single disorder was pronounced which means diseases which are caused by mutation in single genes such as cystic fibrosis or Huntington disease, etc.
  • Yet, at present there is a paradigm switch from individual genes to multiple genes (genomics) and their gene-gene interactions as well as gene-environment interactions (epigenetics).
  • Classification of Medical conditions or diseases linked to genes is done in a number of ways, it can be best classified as:Monogenic (or single gene) disorders; Polygenic (or multi- gene) disorders; and Multifactorial disorders.
  • When a mutation in one or both alleles of a single gene is the causing factor in a genetic disorder is known as monogenic disorders like huntington disease, beta thalassemia.
  • Polygenic disorders – Medical conditions with genetic perspective involves either the interaction of a number of genes (polygenic).
  • Individuals at risk for particular diseases could be identified by comparing the patients genetic pattern with the known patterns form HapMap, it will help researchers to locate the diseases associated blocks or genes.
  • Multifactorial disorders means that a mutated allele inherited for particular conditions complies that the individual is vulnerable or predisposed to develop the condition.
  • Other factors such as diet or stress or exposure to certain environmental factors are involved to ensure the expression of the disease or condition. Common health problems in humans such as heart disease, hypertension, psychiatric illness (such as schizophrenia), dementia, diabetes, cancers etc. are multifactorial.
  • Genetic variations or mutations are commonly presented as ‘diseases’ or ‘disorders’ but in the past, some of these mutations considered to enhance the prospects of survival in certain environmental contexts like carrier state of beta thalassemia is protected against malaria.
  • Issues raised by genomic research include: Ethical standards required to work on human subjects or tissues, possible discrimination by employers and health insurers and consideration of social, cultural and religious perspectives of genetics and health. All these issues are need to be addressed through proper management.
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