Human Genome Project

The purpose of the Human Genome Project was to determine the complete sequence of 3 billion DNA sub-units, identify all human genes and make the information available.

Human Genome Project Information – [ornl.gov]

Completed in 2003, the Human Genome Project (HGP) was a 13-year project coordinated by the U.S. Department of Energy and the National Institutes of Health. During the early years of the HGP, the Wellcome Trust (U.K.) became a major partner; additional contributions came from Japan, France, Germany, China, and others. See our history page for more information.

Project goals were to:

Identify all the approximately 20,000-25,000 genes in human DNA

Determine the sequences of the 3 billion chemical base pairs that make up human DNA

Store this information in databases

Improve tools for data analysis

Transfer related technologies to the private sector

Address the ethical, legal, and social issues (ELSI) that may arise from the project

Insights Learned from the Human DNA Sequence – [ornl.gov]

What has been learned from analysis of the working draft sequence of the human genome? What is still unknown?

By the Numbers

The human genome contains 3.2 billion chemical nucleotide base pairs (A, C, T, and G).
The average gene consists of 3,000 base pairs, but sizes vary greatly, with the largest known human gene being dystrophin at 2.4 million base pairs.

The total number of genes is estimated at 25,000, much lower than previous estimates of 80,000 to 140,000 that had been based on extrapolations from gene-rich areas as opposed to a composite of gene-rich and gene-poor areas.

The human genome sequence is almost exactly the same (99.9%) in all people.

Functions are unknown for more than 50% of discovered genes.

The Wheat from the Chaff

About 2% of the genome encodes instructions for the synthesis of proteins.

Repeat sequences that do not code for proteins make up at least 50% of the human genome.

Repeat sequences are thought to have no direct functions, but they shed light on chromosome structure and dynamics. Over time, these repeats reshape the genome by rearranging it, thereby creating entirely new genes or modifying and reshuffling existing genes.

During the past 50 million years, a dramatic decrease seems to have occurred in the rate of accumulation of repeats in the human genome.

How It’s Arranged

The human genome’s gene-dense “urban centers” are predominantly composed of the DNA building blocks G and C.

In contrast, the gene-poor “deserts” are rich in the DNA building blocks A and T. GC- and AT-rich regions usually can be seen through a microscope as light and dark bands on chromosomes.
Genes appear to be concentrated in random areas along the genome, with vast expanses of noncoding DNA between.

Particular gene sequences have been associated with numerous diseases and disorders, including breast cancer, muscle disease, deafness, and blindness.

Stretches of up to 30,000 C and G bases repeating over and over often occur adjacent to gene-rich areas, forming a barrier between the genes and the “junk DNA.” These CpG islands are believed to help regulate gene activity.

Chromosome 1 (the largest human chromosome) has the most genes (3,168), and Y chromosome has the fewest (344).

How the Human Genome Compares with That of Other Organisms

Unlike the human’s seemingly random distribution of gene-rich areas, many other organisms’ genomes are more uniform, with genes evenly spaced throughout.

Humans have on average three times as many kinds of proteins as the fly or worm because of mRNA transcript “alternative splicing” and chemical modifications to the proteins. This process can yield different protein products from the same gene.

Humans share most of the same protein families with worms, flies, and plants, but the number of gene family members has expanded in humans, especially in proteins involved in development and immunity.

The human genome has a much greater portion (50%) of repeat sequences than the mustard weed (11%), the worm (7%), and the fly (3%).

Over 40% of predicted human proteins share similarity with fruit-fly or worm proteins.

Although humans appear to have stopped accumulating repeated DNA over 50 million years ago, there seems to be no such decline in rodents. This may account for some of the fundamental differences between hominids and rodents, although gene estimates are similar in these species. Scientists have proposed many theories to explain evolutionary contrasts between humans and other organisms, including those of life span, litter sizes, inbreeding, and genetic drift.

Variations and Mutations

Scientists have identified millions of locations where single-base DNA differences occur in humans. This information promises to revolutionize the processes of finding DNA sequences associated with such common diseases as cardiovascular disease, diabetes, arthritis, and cancers.

The ratio of germline (sperm or egg cell) mutations is 2:1 in males vs females. Researchers point to several reasons for the higher mutation rate in the male germline, including the greater number of cell divisions required for sperm formation than for eggs.

What We Still Don’t Understand: A Checklist for Future Research

Exact gene number, exact locations, and functions

Gene regulation

DNA sequence organization

Chromosomal structure and organization

Noncoding DNA types, amount, distribution, information content, and functions

Coordination of gene expression, protein synthesis, and post-translational events

Interaction of proteins in complex molecular machines

Predicted vs experimentally determined gene function

Evolutionary conservation among organisms

Protein conservation (structure and function)

Proteomes (total protein content and function) in organisms

Correlation of SNPs (single-base DNA variations among individuals) with health and disease

Disease-susceptibility prediction based on gene sequence variation

Genes involved in complex traits and multigene diseases

Complex systems biology, including microbial consortia useful for environmental restoration

Developmental genetics, genomics

Applications, Future Challenges
Deriving meaningful knowledge from the DNA sequence will define research through the coming decades to inform our understanding of biological systems. This enormous task will require the expertise and creativity of tens of thousands of scientists from varied disciplines in both the public and private sectors worldwide.

The draft sequence already is having an impact on finding genes associated with disease. Over 30 genes have been pinpointed and associated with breast cancer, muscle disease, deafness, and blindness. Additionally, finding the DNA sequences underlying such common diseases as cardiovascular disease, diabetes, arthritis, and cancers is being aided by the human variation maps (SNPs) generated in the HGP in cooperation with the private sector. These genes and SNPs provide focused targets for the development of effective new therapies.

One of the greatest impacts of having the sequence may well be in enabling an entirely new approach to biological research. In the past, researchers studied one or a few genes at a time. With whole-genome sequences and new high-throughput technologies, they can approach questions systematically and on a grand scale. They can study all the genes in a genome, for example, or all the transcripts in a particular tissue or organ or tumor, or how tens of thousands of genes and proteins work together in interconnected networks to orchestrate the chemistry of life.

Post-sequencing projects are well under way worldwide. (See Genomics:GTL). These explorations will result in a profound, new, and more comprehensive understanding of complex living systems, with applications to agriculture, human health, energy, global climate change, and environmental remediation, among others.