The Human Genome Project seeks to understand the genetic essence of the human species

How the Human Genome Project will sequence the 3 billion pairs of chemical bases that make up our DNA strands

By Jerold M. Lowenstein|Friday, May 01, 1992
RELATED TAGS: GENETICS
The Human Genome Project was officially launched in 1990 with the ambitious goal of understanding the genetic essence of the human species. It intends to achieve that goal by sequencing the 3 billion pairs of chemical bases that make up the spiraling DNA strands inside the nucleus of each of our cells. Together these bases spell out a fantastically long message--equivalent in length to 13 sets of the Encyclopaedia Britannica-- programming the birth, development, growth, and death of a human being. Once the message is deciphered, it’s expected to be the ultimate sourcebook for understanding human biology and inherited diseases.

The project will take about 15 years and cost $3 billion. There are some 5 billion humans on Earth today. Whose genome or genomes will be immortalized by this massive effort, an undertaking that has been called the moon shot of biology?

There was speculation that the First Genome might appropriately be that of James Watson--after all, he is the project’s overall director and codiscoverer of DNA’s helical shape. One biologist jokingly told me he hoped the First Genome would be Ronald Reagan’s because so much would be missing that it would be relatively easy to sequence. Sequencing a stretch of DNA literally means finding the consecutive order of its chemical bases- -designated by the letters A, C, T, and G--and writing them out. (A typical sequence goes TACCGTTAAAGCATG. . . .) Deciphering short pieces of DNA is relatively simple. But doing a whole gene, which may go on for 30,000 bases, is much more difficult. Sequencing an entire genome, which has between 50,000 and 100,000 genes and some 3 billion bases, is something else again.

Most project participants have dismissed the whose genome question as irrelevant, stating that the final map and sequence will be a composite of information from hundreds of individuals. But recently Luigi Cavalli-Sforza of Stanford and the late Allan Wilson of the University of California at Berkeley complained that the project as presently conceived will be strictly Caucasian, a squeezy-white-bread genome. They made an impassioned plea for funds to collect and study genetic material from some of the hundreds of indigenous peoples, such as African Pygmies and Amazonian Indians, who are rapidly disappearing or being overrun by their neighbors.

How much difference does it make whose genome is sequenced? The answer to this question requires a consideration of the evolutionary status of the human species.

Like all life on Earth, we are the product of more than 3 billion years of evolution. During that very long period the biochemical machinery of life and reproduction has changed remarkably little, but the forms of life have diversified and become more complex. The smaller genomes of simpler forms will help us understand the architecture and organization of our own. For that reason the Human Genome Project will include studies of various honorary humans, as they’ve been dubbed: the bacterium Escherichia coli, the nematode worm Caenorhabditis elegans, and the fruit fly Drosophila melanogaster.

The fruit fly genome, which is roughly one-twentieth the size of ours, contains about 4,000 genes. More than 400 of them have already been identified as being very similar to ours. This tells us that humans and flies descended from a common ancestor. That ancestor, which was some kind of insect, lived about half a billion years ago. We’re all relations under the cell membrane, and the things we will learn from the fly and the worm will help us enormously in deciphering the contents of our own cell nucleus.

Mammals have been around for some 200 million years, but modern placental mammals like us seem to have had a common ancestor about 65 million years ago. Naturally, we are genetically much more like mice, dogs, horses, and other placental mammals, which give birth to live young, than we are like flies and worms. Our DNA is only 20 percent different from that of a mouse. So in sequencing the human genome we will be sequencing about 80 percent of the genome of other placental mammals as well.

We humans, of course, are primates as well as mammals. Our closest living relative is the chimpanzee, whose genome differs from ours by only 1 percent. This difference reflects changes accumulated during the 5 million years since our divergence from a common African primate ancestor. To creationists, who don’t believe in the ape-human connection at all, it is ego-shattering to contemplate that the chosen species, made in God’s own image, is genetically 99 percent identical to the chimpanzee.

And ironically, despite our pride in human individuality, we are an unusually homogeneous species. On average, two people of the same sex differ in their DNA by only one-tenth of 1 percent. Even Dan Quayle and Linus Pauling would be 99.9 percent identical if you were to compare their genetic material. Chimps, the true individualists, average six times that much difference among themselves.

That’s because the longer a group has existed, the greater its diversity. Thus it appears that chimps have been around six times as long as modern humans. When different geographic and ethnic groups of humans are compared, those of African origin exhibit more gene diversity than those of Caucasian or Asian origin. From this it can be deduced that Homo sapiens originated in Africa about 200,000 years ago and later spread to the rest of the world. (Although the African Eve theory has come under attack since it was first proposed, the weight of accumulated data, including the fossil evidence, seems to continue to support it.)
This revelation (by Rebecca Cann, Allan Wilson, and their co- workers at Berkeley), that humans had a comparatively recent African origin, shocked a great many anthropologists. They had assumed that all modern humans descended from Homo erectus, a hominid lineage that left Africa a million years ago. According to the older scenario, different groups of Homo erectus evolved separately into Homo sapiens in Africa, Asia, and Europe. But this hypothesis just doesn’t fit the DNA data. If the old scenario were correct, you would expect human DNA to be much more diverse than it is. In other words, we would be more individualistic, like chimps, rather than being as similar to each other as we are.

Still, .1 percent of the 3 billion base pairs in human DNA amounts to 3 million--quite enough genetic difference to account for all the individual and racial variability that we observe among our species. One purpose of the genome project is to create a template that will help us find out how particular variations in chemical base sequence lead to differences in skin and hair color and height, as well as in susceptibility to disease.

So it does make some difference, a tiny but crucial .1 percent or less, whose genome is being sequenced and written out in a very long string of ACTGs. But no matter whether you start with Wilt Chamberlain or Danny DeVito, you’re going to get 99.9 percent of an average human genome. (Bear in mind, too, that you’re going to get typos, as you always do in copying cryptic manuscripts or any laboriously long text. It turns out that even in the very best hands, the error rate in DNA sequencing is about .1 percent, which will add as much slop to the sequence as 200 millennia of modern human evolution have done.)

So now let’s consider the hypothetical personage whose genome will be the first to be encyclopedically transcribed, errors and all. We’ll call him Hugo, the acronym for the Human Genome Organization, one of the leading groups involved in the project.

A feminist friend of mine complained that naturally Hugo would be a male, given the male bias of scientists, but actually there’s a reason for the choice. Both males and females have their DNA distributed on 23 pairs of chromosomes. But females have two X chromosomes, while males have an X and a Y. Since a complete genome sequence requires both an X and a Y, Hugo must inevitably be male.

Not only will Hugo be male, he will have a decidedly Gallic accent. Thanks to Nobel laureate Jean Dusset, the Center for the Study of Human Polymorphism, in Paris, has collected cell lines from more than 60 different three-generation families that include all four grandparents, two parents, and eight or more grandchildren. The French group provides high- quality DNA of known lineage to investigators throughout the world, and this material has been invaluable for finding out which genes are located on which chromosomes and for developing the initial map of gene topography that precedes actual sequencing.

Since getting to know Hugo is such a big job, it is being tackled by numerous groups. Some are focusing on particular chromosomes, just as explorers of past centuries took on particular islands or continents, or as present satellite voyagers take on different planets in our solar system. And hundreds of teams throughout the world are searching for specific genes, like the recently discovered gene for cystic fibrosis or the gene for Huntington’s chorea, a fatal neurological disorder. In fact, as of now some 400 of the 2,000 genes that have been mapped on particular chromosomes are disease-related. Obviously, then, a lot of Hugo’s composite genome will be derived from people with genetic diseases, since finding the basis of the diseases, with the eventual hope of curing them, is one of the major justifications for all the effort and money.

Who then will Hugo represent 13 years down the line when the Human Genome Project has accomplished its mission? Whose DNA footprints will we see when the moon shot of biology has landed?

Hugo’s genome, whatever its multiple sources, will be about 99.9 percent identical with the genomes of every other human being on Earth. It will be 99 percent the same as a chimpanzee’s, 90 to 95 percent the same as those of other primates, and 80 percent similar to those of other mammals. And hundreds, even thousands, of its genes will be very much like those of all other forms of life on Earth--honorary humans all--including bacteria, fungi, plants, worms, and insects.

Hugo will not only be Everyman and Everywoman, but in a sense Everyterrestrial--a testimony to the common origin and interrelatedness of all life on Earth.
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