31 Applied Human Genetics

Dr. Sanjenbam Meitei

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Contents of this unit

Introduction

1. Population Variation

2. Medicine and Healthcare

a) Genetic screening

b) Genetic epidemiology

3. Personal Identification

4. Archaeogenetics Summary

 

 

Learning Objectives

  • What are the scopes of human genetics?
  •  What could be the role of genetic traits in population variation?
  • How could the inter population variation leads to varied prognosis of complex disorders?
  • What are the major areas of healthcare that human genetics can be applied for?
  • What would be the effect of technological advancement in this subject matter especially in case of forensic application?
  • What could be the source of genetic information from archaeological remains?

 

Introduction

Genetics has become an important part of our daily life. As we know that genetics is about the inheritance of genes from parental generation to next generation and also it is associated with expression of phenotype from genotype. This basic concept of genetics can be applied to a number of basic or applied researches as such, or it can be controlled or modified to get the desired result so. In fact, the application of human genetics has become more broaden in the post genomic era. Applied genetic researches are usually carried out to dig upon practical problem or to implement for the better human society such as genetic predisposition of certain disease, solving the human evolutionary queries, forensic application etc. In this module, some of the important application of the same is discussed.

 

1. Population variation

The concept of genetics has been applied in exploring the human genetic variation, and hence depicts the population history or evolutionary framework of biological species. Individuals in a Mendelian population share a common gene pool that can be traced back to their ancestors. Every population has its own genetic structure which can be defined as the distribution of alleles and genotypes in the population. Statistical inferences play a crucial role in reconstructing the evolutionary framework. The basic principle in this approach lies in the concept that evolution could be constructed by analyzing the multilocus genotype on a chromosome observed in populations and their inheritance within families (Race and Sanger, 1975).

 

Genetic variations in both inter and intra populations are studied through certain selected genetic markers. Genetic markers can be either serological or biochemical traits. In the post human genome project, genomic markers are more considered as more reliable tools for studying human genetic variation. There are certain basic characteristics to be considered for genetic markers, such as locus specific, polymorphic and easily genotyped. It is through these genetic variations that one’s population structure can be determined, and at the same time inter or intra population variation can also be evaluated through certain statistical models. Phylogenetic relationship of the population can also be determined based on the genetic similarities and differences. Consequently, exploring human genetic variation has become one of the important applications of human genetics and thereby trying to give an insight on the human evolution and earliest migration.

 

Moreover, the knowledge of human genetic variation can also be applied in understanding the roles of genetic variation in the development and progression of complex disorders all over the world population. It is assumed that the patterns of genetic variation shed light on recombination, demography, admixture, and evolutionary selection in the human population, and thereby projecting the underlying genetic manifestation of the diseases varied population wise. Further, population heterogeneity may lead to spurious associations while examining the genetic role in disease progression. It is hereby noteworthy to mention that good knowledge of population genetics or population structure is much needed in understanding the genetic mechanism of disease progression which may differ from population to population (Meitei et al., 2012).

 

2. Medicine and Healthcare

Genetic technology is now an important part of medicine, and its impact will continue to grow as information from genomics is analyzed and applied to the diagnosis and treatment of human diseases (Cummings, 2010). Genetics has a very important role in medical aspects thereby promoting healthcare; hence an independent discipline has been emerged as medical genetics. With the concept of one gene one enzyme, the importance of gene in development of Mendelian disorders or classical single gene disorders cannot be ignored, as diseases can result from altered proteins or too little or too much of a protein, or proteins made at the wrong place or time (Lewis, 2009). Moreover, various complex disorders are now considered as the consequences of the interaction of gene and environment, even the inherited ones are sensitive. Some of the application of genetics in medicine and healthcare could be analyzed as such:

 

a)  Genetic screening and counseling: Screening of various genetic disorders – both single gene and complex disorders is very much essential for the promotion of common healthcare. There are a number of inherited disorders which are lethal or sub-lethal. Screening of such lethal or sub-lethal disorders is one of the important applications of human geneticists. It is expected that millions of people worldwide are affected to such genetic disorders with over 10000 monogenic inherited disorders (http://www.who.int/genomics/public/geneticdiseases/en/index2.html) and every newborn has a 3% chance of having a genetic disorder, underscoring the need for tests that accurately diagnose heritable diseases at all stages of life (Lewis, 2009). These monogenic disorders may be autosomal or sex linked inheritance in either dominant or recessive patterns. Dominant inheritance will result into the expression of phenotype or disorders in question even in presence of only one copies of mutant allele. While for recessive traits, two copies of mutant alleles are needed to express the phenotypic trait. The concerns of human geneticists in this regard lies in the identification of early prognosis of such lethal or sub genetic traits especially among the newborns, and hence remedial measures can be planned through counseling.

Figure 1: Flowchart indicating steps involved in Genetic Counseling (Lewis, 2009)

 

Genetic counseling is the process by which the patients or relatives at risk of an inherited disorder are advised of the consequences and nature of the disorder, the probability of developing or transmitting it, and the options open to them in management and family planning. This complex process can be separated into diagnostic (the actual estimation of risk) and supportive aspects (Sequeiros et al., 2012). The person who is giving advice is the counselor and the person who is seeking is counselee. Counselors need special attention in case of monogenic recessive disorders such as cystic fibrosis, phenylketonuria etc. as the normal couple has the probability of giving birth to affected children in the condition that both are carriers of the disorders. Early prognosis of such disorders is very much essential for the babies. Besides the monogenic inherited disorders, the counselors also deals with the complex disorders and the probable interaction of environment and gene based on the incidence of family history of the disorder. Though the counselors talk about the causes and consequences of genetic disorders, it is the counselee who has to take the final decision in this matter. A counselor can’t insist the counselee to opt or decide in favour of him.

 

b) Genetic epidemiology:

 

Figure 2: Interrelationship of Population Genetics and Genetic Epidemiology through population structure and inter population variation

 

Epidemiological studies is one of the another important application of genetics in the field of health sciences. According to John Hopkins Bloomberg School of Public Health, Genetic Epidemiology is the study of how genetic factors contribute to health and disease in families and populations, and how genes interplay with environmental factors (http://www.jhsph.edu/departments/ epidemiology/tracks/genetic-epidemiology/). So, it can be inferred that it is the study of interaction of genes and environments on health and disease risk in populations, which is very resemblance with Anthropological approach of ‘Nature-Nurture’ interaction. Genetic epidemiologists attempt to identify the many components of risk attributable to genes, environments, and interactions between these two factors in the progression and manifestation of various disorders, especially of the complex one. In the post human genome era, technological advancement such as implementation of genome-wide association studies, sequencing etc., have brought a new dimension in the biomedical research with identification of various disease susceptibility loci and interaction among each other in the phenotypic expression of the traits under concerned. Moreover, the epigenetic approach also contributes understanding to the role of gene and its associated factors in the varied disease expression. Genetically no two individuals are identified, similarly one Mendelian population differ from each other in terms of its genetic structure. Individuals in a population are believed to share a common gene pool, and hence disease susceptibility loci are more or less common among the individuals of the same population. Here, the importance of population genetic variation lies in analyzing the disease susceptibility loci in different population and so forth different disease management programme can be taken up. The interaction of human genetic variation in epidemiological approach is well evident through demographic parameters (Figure 2) as the changing demographic aspects (i.e. mating patterns or admixing) may transform the population’s gene pool, which in turn could switch on/off the clinically important risk alleles (genes) and thereby affecting the community health with complex disorders.

 

Metagenomics studies are also a part of genetic epidemiological approach. The role of microbes and its genome in understanding the overall human health can’t be ruled out. Metagenomics, the study of genetic material recovered directly from environmental samples, has emerged as a powerful tool that can be used to analyze microbial communities regardless of the ability of member organisms to be cultured in the laboratory. Metagenomics could also unlock the massive uncultured microbial diversity present in the environment to provide new molecules for therapeutic and biotechnological applications (http://www.nature.com/nrmicro/focus/metagenomics/index.html). The application of met genomics can be more clearly understand in the context of human nutritional studies. Nutrients are important basic needs for human body functioning, but the problem lies that at the present the world is witnessing dual faces of nutrition – under nutrition and over nutrition, which both are harmful to the human health. Absorption and digestion of nutrients have biological implications. The microbes present in the intestinal tract have a major role in the overall process. The interaction of microbes and its genomic contents need to assess to address the human nutritional problem (Ahmed et al., 2009)

 

3. Forensic genetics

Personal Identification is one of the important objectives in forensic investigation on the grounds of medico-legal context. Identification can be done through different biological traits, but genetic traits give more precise information in this aspect. It is already established fact that no two individuals are completely identical and this inter individual variation is more apparent when genetic analysis is made. It may be case of paternity disputes or identification of victims or culprits involved in any forensic related issues, could be solved through genetic identification. The application of genetics in the medio legal context for identification of persons involved in it is referred as Forensic genetics.

 

In earlier, classical genetic traits have been employed for the same but in the post genomic era, DNA profiling known as DNA fingerprinting have been used quite extensively. DNA fingerprinting also popularly known as DNA profiling is a specialized method to analyze, compare and identify multilocus DNA banding patterns that are specific to an individual by exposing a sample of the person’s DNA to molecular probes and various analytical techniques (The American Heritage Medical Dictionary, 2004). It was first discovered by Prof. Alec Jeffreys in the year 1984 (http://www2.le.ac.uk/study/why-us/discoveries/the-invention-of-dna-fingerprinting). Biological sample can be collected from different sources such as buccal swab, blood, saliva, semen any cellular materials and further analysis like DNA extraction, amplification and genotyping are done. Through DNA profiling, victim identification even in natural disasters, tragedies such as plane crashes, man-made disasters such terrorist attack or genocide can be done. It is reported that DNA profiling been rarely used before September 11, 2001 but after the incident of World Trade Centre fall, it becomes an important tool for personal identification even in the case of missing people (Lewis, 2009). The well publicized case of Congress veteran leader ND Tiwari can be cited over here (http://www.rediff.com/news/report/n-d-tiwari-s-dna-report-to-be-made-public/20120727.htm). Prior to the arrival of DNA profiling, identification can be assessed from serological traits blood group etc. As an example, in the case of paternity dispute, the probable father of an illegitimate child can be found out by comparing the blood groups of mother, child and suspected father. It is based on the inheritance of blood group as O blood group parents can’t have A or B blood group child.

 

 

4. Archaeogenetics

Human evolution itself is a mystery. There are lots of obscurities that need to be explored to have an overall illustration of human evolution. Different stages have been constructed based on the fossil evidence, though there are missing links which hasn’t been rectified yet. In fact, the relationship or interaction between the extinct and extant hominids hasn’t been clearly depicted. The emergence of population genetics in the evolutionary biology particularly in the human evolutionary studies led to the development of new discipline ‘Archaeogenetics’ with which explains the human past through molecular population genetics. It is defined as defines as the study of the past by use of the techniques of molecular genetics (Renfrew and Boyle, 2000). This discipline targets to collect genetic information from the fossil hominids, makes it compared with those of present living human population groups and tries to decipher the genetic relationship of extinct and extant human population and overall the probable relations with the environmental factors through statistical models. Different studies have been come up from Europe as a number of archaeological sites are discovered in the nineteenth and twentieth century (Trigger, 1979). The issues related with the human early demographic history are the main concerns of the Archaeogenetics. Besides this, it also concerns with the archaic pathogens that affects the health of extinct human through historical epidemics. The significance of Archaeogenetics lies in the concept that it can shed light on the origins and geographical spread of prehistoric languages and also assist archaeologists in answering questions regarding the influence of population growth in the archaeological record (Forster and Renfrew, 2006). As an example, mt DNA analysis of modern populations of South Asia, East Asia and Oceania reveals that there was large population expansion before the advent of microlith technology. Through molecular clock analysis, this expansion was dated to 38-28 ka ago [kiloannus (ka): a unit of time equivalent to 1000 years] while microlith technology is expected to started from 35–30 ka ago (Petraglia, 2009).

 

In summarizing the contents, the application of human genetics is increased beyond the horizon. Biotechnological application of the same improvises the quality of human life by providing genetically modified food crops. It also formulates the substratum for new diagnostic tests, or synthesis of customized proteins for treating certain disease or production of vaccines in medical arena. It enhances the concept of community health and also assist in the population specific drug designing ‘pharmcogenomics’ based on the concept that every population have unique gene pool.

 

Summary

  •  The application of human genetics in the present day world is vast.
  • Gene pool of a population can be traced back to their ancestors.
  • Evolution could be constructed by analyzing the multilocus genotype on a chromosome observed in populations and their inheritance within families.
  •  Genetic markers can be either serological or biochemical traits.
  • Genetic markers should be locus specific, polymorphic and easily genotyped.
  • Patterns of genetic variation project the underlying genetic manifestation of the diseases.
  •  Complex disorders are now considered as the consequences of the interaction of gene and environment.
  • Screening of lethal or sub-lethal disorders is one of the important applications of human geneticists.
  • Genetic counselling is the process by which the patients or relatives at risk of an inherited disorder are advised of the consequences and nature of the disorder, the probability of developing or transmitting it, and the options open to them in management and family planning.
  • Genetic epidemiologists attempt to identify the many components of risk attributable to genes, environments, and interactions between these two factors in the progression and manifestation of various disorders, especially of the complex one.
  • Disease susceptibility loci are more or less common among the individuals of the same population sharing gene pool.
  • Absorption and digestion of nutrients contributes to the manifestation of nutritional status of the individual.
  • The microbes present in the intestinal tract have a major role in the nutritional health.
  • DNA profiling is latest technique for the identification of persons in the context of medico-legal issues.
  • Archaeogenetics reconstruct the genetic relationship of extinct and extant human population and overall the probable relations with the environmental factors.
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References

  • Ahmed, T., Haque, R., Shamsir Ahmed, A.M., Petri, W.A. Jr, Cravioto, A. 2009: Use of metagenomics to understand the genetic basis of malnutrition. Nutr Rev. 2009 (67) Suppl 2: S201-6.
  • Renfrew, C. and Boyle, K. (Eds) 2000: Archaeogenetics: DNA and the Population Prehistory of Europe. Cambridge: McDonald Institute for Archaeological Research.
  • Cummings, M.R. 2010: Human Heredity, CA: Cengage Learning.
  • Forster, Peter; Renfrew, Colin, eds. (2006). Phylogenetic Methods and the Prehistory of Languages. Cambridge, UK: McDonald Institute for Archaeological Research.
  • Lewis, R. 2009: Human Genetics – Concepts and Application, New York: McGraw Hill.
  • Meitei, S.Y., Saraswathy, K.N., and Sachdeva, M.P. 2012: Demogenetic study – A holistic approach for studying population structure. International Journal of Human Sciences (9)2, 392-404.
  • Petraglia, M. 2009. Population Increase and Environmental Deterioration Correspond with Microlithic Innovations in South Asia ca. 35,000 Years Ago. National Academy of Sciences 106 (30): 12261–12266.
  • Race, R.R. and Sanger, R. 1975: Blood Groups in Man. Oxford: Blackwell Scientific.
  • Sequeiros, J., Paneque, M., Guimaraes, B., Rantanen, E., Javaher, P., Nippert, I., Schmitdke, J., Kaariaainen, H., Kristoffersson, U and Cassiman, J.J. 2012: The wide variation of definitions of genetic testing in international recommendations, guidelines and reports. J Community Genet. 3(2): 113–124.
  • The American Heritage Medical Dictionary 2004. US: Houghton Mifflin Company.
  • Trigger, B.G.1989: A History of Archaeological Thought. UK: Cambridge Univ. Press.
  • Speicher, M.R., Antonarakis, S.E. and Motulsky, A.G. 2010: Vogel and Motulsky’s Human Genetics. Heidelberg: Springer.
  • Thomas, D.C. 2004: Statistical Methods in Genetic Epidemiology. New York: Oxford University Press.
  • Cavalli-Sforza, L.L. and Feldman, M. 2003: The Application of Molecular Genetic Approaches to the Study of Human Evolution. Nature genetics Supplement 33: 266-275.
  • Jablonka, E. and Lamb, M.J. 2002: The Changing Concept of Epigenetics. Ann. N.Y. Acad. Sci. 981: 82–96.
  • Lewis, R. 2009: Human Genetics – Concepts and Application, New York: McGraw Hill.
  • Morton, N.E. 1982: Outline of Genetic Epidemiology. New York: Karger Publication.
  • Pasternak, J.J. 2005: Human Molecular Genetics, NJ: Willey-Liss

Web references

  • http://www.jhsph.edu/departments/epidemiology/tracks/genetic-epidemiology/
  • http://www.nature.com/nrmicro/focus/metagenomics/index.html
  • http://www.rediff.com/news/report/n-d-tiwari-s-dna-report-to-be-made-public/20120727.htm
  • http://www.who.int/genomics/public/geneticdiseases/en/index2.html
  • http://www2.le.ac.uk/study/why-us/discoveries/the-invention-of-dna-fingerprinting
  • http://www2.le.ac.uk/study/why-us/discoveries/the-invention-of-dna-fingerprinting