Human Genome Project 

The human genome project was an international effort to sequence every nucleotide in the human genome and to identify all the genes contained within the genome. This effort was coordinated by the United States Department of Energy and National Institutes of Health (NIH). It was the highest ever funded programme in biology and laboratories from UK, Japan and Germany were also associated with it. 

1.0Introduction

• The double helical structure of the DNA molecule was proposed in 1953 (Watson and Crick, 1953) and with that molecular biology provided the physical basis for the inheritance of genetic information from one generation to the next. By this time DNA was known to be self-replicating machinery. 
• The knowledge of the double helical structure helped understand the mechanics of replication. 
• Each strand of the DNA molecule is capable of resynthesizing a complementary strand, and the resulting strands intertwine with the help of hydrogen bonds to produce two daughter DNA molecules. 
• In addition, genomic DNA in a cell was known to be of a finite length. 
• The nuclear DNA encoded for all the molecular information required to build a cell or the whole organism. 
• Deciphering the sequence of the genomic DNA of humans was perceived to help generate the coded information of the structure and metabolism at the cellular and organismal level. 
• These three factors sowed the seeds of the idea behind the first ever human genome project which was aimed at finding the sequence and composition of the deoxy-ribonucleotides of the DNA molecules that comprise the entire human genome. 
• The technological prowess required for genome sequencing brought together public and private partnerships involving the best minds in molecular biology. Before delving into genome projects lets go through the evolution of genome mapping.

2.0Role of Bioinformatics in Genome Projects

• The branch of biology dealing with acquiring, storing, managing, displaying and analyzing massive amounts of biological data is called bioinformatics. Biological data is available as nucleic acid and amino acid sequence data. 
• The huge amount of nucleic acid data produced as a result of genome projects in general and human DNA sequence data produced by human genome projects, invited bioinformaticians to play an emphatic role in the projects. 
• Bioinformatics tools first came into use after generation of sequences by the sequencers. 
• The DNA sequences were assembled after identification of overlapping areas in a series of sequences. 
• The computer programs used are called sequence assembly software. In addition, the sequence data is viewed as essential to researchers studying genetic diseases in humans. 
• Thus the annotation of gene sequences to establish their functions and development of preventive, diagnostic and therapeutic strategies for diseases were important responsibilities of bioinformatics post genome sequencing. 
• After establishing gene functions appropriate programs are used for comparing gene structure and functions in different organisms, examine genetic variation within and between species to explore phylogenetic relationships. 
• All these diverse roles have made bioinformatics an ever-expanding field with new software being developed almost every day

3.0Genome Sequencing

• The chromosome comprising a single DNA molecule is the starting unit for genome mapping. Individual chromosomes are treated with certain dyes to get distinct chromosome banding patterns. 
• These patterns are used to generate cytological maps for each chromosome. These maps are used to locate structural modifications in chromosomes. Isolated single stranded DNA fragments are located on chromosomes by labeling the fragments with fluorescent probes and hybridizing to chromosomes. 
• The fragment hybridizes to its complementary sequence on the chromosome. This method is called fluorescence in situ hybridization (FISH).

4.0Genetic Mapping

• A genetic map is a representation of the distance between two DNA elements obtained using the recombination frequency between the two. 
• The construction of the first genetic map for Drosophila by Alfred Sturtevant was in fact the conception of the idea of mapping genomes. 
• Genetic maps can be constructed for each chromosome of an organism. Demerits of this method are that the gene to be mapped should be coding for an observable phenotype and a number of crosses are required to generate enough data for mapping. 

5.0Physical Mapping

• The physical map of a genome is a map of genetic markers made by analyzing a genomic sequence directly rather than obtaining recombination frequencies first. 
• Restriction mapping, radiation hybrid maps and STS maps are some examples of physical maps. 
• The physical maps have been useful in producing a definite order of cloned fragments of DNA but not useful for finding the DNA sequence. Finding the DNA sequence is the final step of a genome sequencing project. 

6.0Overview of the First Human Genome Project

• Human Genome Project (HGP) pioneered human genome sequencing on a large-scale by aiming to completely sequence the human genome and make the data generated freely available to researchers. 
• It was a co-ordinated effort by the National Institute of Health (NIH) and Department of Energy (DoE) in the USA to decode the sequence of the complete human genome. The main goals of the project were:
• To generate comprehensive maps of the location of genes in the human genome and in those of other well studied model organisms in biology like bacteria, yeast, nematode, fruit fly, mouse and Arabidopsis thaliana. 
• To determine the nucleotide composition and sequence of the DNA of the genomes of model organisms mentioned above and to identify and annotate functions of the 20,000 human genes estimated to be present in the human genome using the genetic information from the organisms. 
• The genomic information is in the form of nitrogenous bases named A for Adenine, T for Thymine, G for Guanine and C for Cytosine. 
• To store the information generated in databases freely available for public viewing and research 
• To improve tools for sequencing data analysis through computational methods 
• The project targeted identification of all the genes, creation of a database for cataloguing the sequences of the individual chromosomes, development of faster, high throughput sequencing methodologies and investigating the ethical, legal and social complications that crop in genome sequencing efforts. 
• The first draft of the human genome sequence was published in 2001 by the International Human Genome Sequencing Consortium which covered 90% of the complete sequence. The complete sequence for Drosophila (fruit fly) was also available. 
• The final sequence was announced in April, 2003. The feat of the complete sequencing of the human genome was achieved in record time due to the development of the whole genome shotgun sequencing technique by a biotechnology company Celera Genomics. In this technique the entire genome is fragmented randomly. 
• Following which each fragment is amplified by cloning in a vector. Each vector insert is then sequenced separately using an automated sequencing machine. 
• The sequences are then examined for overlapping and assembled to get the complete genome. 
• The achievements of the project were:
• The shotgun sequencing technique developed was subsequently adopted for sequencing genomes of organisms to delineate their phylogenetic relationship with humans.
• The HGP provided information on the structure, organization and function of the set of human genes comprising about 20, 500 genes. 
• Comparative genome sequencing complemented efforts to annotate gene functions which were already being done through studies on gene-knock out animal models and made the process faster and economical.
• Modified from Robert H. Waterston Large regions of DNA in eukaryotic genomes containing heterochromatic DNA could not be sequenced as they were rich in repeat sequences and had fewer genes.
• So although the goal of the project was to obtain a complete sequence for each chromosome, a full sequence has not been obtained till date. 

7.0Ethical, Legal and Social (ELS) Issues

• The realization of possible misuse of genetic information is as old as the generation of human genetic information and hence the related issues are central to all the genome projects. 
• It is believed that genetic information on a certain group of individuals can be used in ways that can create a bias against them. Additionally there are concerns on who should be allowed to access this information. 
• Hence, the brains behind the human genome projects explored the Ethical, Legal and Social Implications (ELSI) of generation of human genetic information. 
• Ethical issues arise from concerns related to what actions are considered right in the successful functioning of an organization which can be a group of individuals or an entire community. 
• Legal issues concern protection of laws that govern ethical concerns. Social issues encompass concerns regarding effect on individuals and entire communities. 
• The main issues concern privacy of genetic information, genetic testing and psychological issues. The National Human Genome Resources Institute (NHGRI) heads the ELSI research programs. 
• It states four categories of the ELSI research program depending on the nature of issues encountered. 
• Psychosocial and ethical issues in genomics research Areas in genomics research that require interventions by the ELSI programs are related to procuring consent of participants, use of cell lines, community participation, data sharing and security, privacy rights, third party benefits from genomics research, use of tissue and health data from the deceased and ethnicity variables in genomics. 
• Psychosocial and ethical issues in genomic medicine Areas in genomic medicine having ELSI relevance are genomic and genetic services for diseased subjects and third parties involved, personalized genomic-based health care, informed consent for communicating genetic information, genomics in preventive care and shift in the roles of healthcare personnel and genomic medicine is implemented. 
• Legal and public policy issues ELSI research includes studies on topics having legal and public policy ramifications like intellectual property rights issues, regulations governing genetic testing, pharmacogenomics and genome-based therapies, ownership and liability issues of biobanked samples, access and use of genetic information by life, disability and long term care insurance companies and use of genomic information for forensic investigation. 
• Broader societal issues ELSI research has profound implications on society. The areas affected are risk and benefits of genomics research availed by communities, genomics research on special populations like newborns, disabled persons, deceased individuals etc., comparative perception of the genetic information of health among individuals, health providers and health care industry, aftermath of comparative genomic research and evidence of natural selection among human populations. 
• The ELSI program ensures privacy of genetic information of an individual and restricts misuse of genetic data like in genetic enhancement to have offspring with desirable traits. The effects of genetic testing on individuals, families and communities as a whole are also monitored to prevent biases against them during provision of medical services. 
• The program also checks inclusion of informed consent of participants in genetics research. It is the prerogative of a researcher to educate the participants about elementary genetics and its effect on health. Genetic research projects are hence under immense scrutiny due to ELS issues related to them. 
• As human genome projects are progressing to accumulate more genomic resources the ELS issues are challenging as ever. In the Indian context, the research on ELS issues is all the more complex with a large number of communities demarcated by social and cultural barriers. 
• With the DNA bill drafted in the monsoon session of Indian Parliament in 2015 the issues will now be talked about outside the restricted group of genetic researchers. The different genome sequencing projects have been summarized in the Table.

• The evolutionary anthropologist Mark Stoneking wrote about the various outcomes of genome projects that will be useful by molecular anthropologists: 
• Mitochondrial DNA sequence helped find the recent origin of the human mtDNA ancestor and subsequently use the information for analysis of human mtDNA variation and evolution. 
• Human genome projects will permit molecular anthropological studies to study evolutionarily important regions of the genome. 3. 
• Knowledge of polymorphisms of disease genes will be facilitated by human genome projects. 
• Development of new technology will help link genetic variation with morphological variation. 
• Comparative genome sequencing of non-human primates to identify genes involved in the morphological differences between human and non-human primates.