The Two Versions of the Human Genome BIOLOGY & MEDICINE Molecular Genetics
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The Two Versions of the Human Genome BIOLOGY & MEDICINE_Molecular Genetics Sequenced, yes – but decoded? We still don’t fully understand our human genetic make-up. The answer to many of its mysteries lies in the diploid nature of the genome, which contains two sets of chromosomes: one inherited from the father and one from the mother. Margret Hoehe from the Max Planck Institute for Molecular Genetics in Berlin has sequenced both versions of the human genome separately for the first time and, in the process, discovered that individuals are even more individual than we thought. TEXT CATARINA PIETSCHMANN hen Margret Hoehe ex- occurred again in particular propor- plains her work, you tions – a phenomenon that can be ex- quickly realize how log- plained only by the existence of two ical her approach is, sets of chromosomes. how obvious – so much W so that you wonder why someone else GENES FROM FATHER didn’t do what she has done a long AND MOTHER time ago. Maybe the reason is that, when one is too close to something, it’s Even if the crosses are not always as easy to lose sight of the big picture. clearly predictable in humans, we have Looking through a magnifying glass, one thing in common with many oth- one might see a craggy grey landscape er organisms: every individual has a ge- and have no idea what it is. Taking a nome that consists of two different sets few steps back, you want to shout to of chromosomes. As a result, all genes them, “Put the magnifying glass down! arise in duplicate: one on the maternal Then you’ll see that what you’re look- chromosome and the other on the pa- ing at is a full-grown elephant.” ternal one. Scientists refer to the differ- Margret Hoehe is one of the few ent parental sequence versions of each people who did just that: took a few chromosome as haplotypes. Chromosomes at the steps back to get a better view. She re- A less well known fact is that, as far moment of cell division: The human genome consists flected on the genetic principles, with- back as 1957, American biophysicist of two sets of chromosomes, out which Gregor Mendel’s laws of the Seymour Benzer demonstrated in a sim- one from the father and inheritance of traits can’t be under- ple experiment that it makes a differ- one from the mother. There stood, and without which no biology ence whether two different mutations are thus two versions of each chromosome. A special lesson is complete. Mendel crossed ho- of a gene are located on the same chro- staining method creates a mozygous pea plants that had either mosome or whether they reside on op- characteristic band pattern purple or white flowers. The plants in posite chromosomes. But Benzer’s dis- for each chromosome, so the daughter generation all had purple covery was forgotten. that the pairs can be flowers, because the gene for purple So wouldn’t it make sense to look at identified on the basis of their comparable size, form flower color was dominant. In the third the two versions of the genome sepa- Photo: SPL-Agentur Focus and color. generation, purple and white flowers rately? Up to now, only “one” genome 1 | 12 MaxPlanckResearch 65 BIOLOGY & MEDICINE_Molecular Genetics Cis configuration Trans configuration Defective Intact Defective Defective The distribution of mutations in a pair of chromosomes can dictate health and disease: In the cis configuration, two mutations arise in one and the same gene form, and the associated protein becomes perturbed. The second copy and the protein originating from it remain unaffected. In the trans configuration, in contrast, both gene copies are mutated and produce two damaged proteins. has been read, a sort of composite of done practically nothing but write In the years that followed, medicine the maternal and paternal sequences. since August to get all of the analyses clearly made progress, but the great There are historical reasons for this: down on paper. breakthrough never came. This may When the Human Genome Project was Why is it important to know how change now with Margret Hoehe’s hap- carried out in the 1990s, it was almost certain mutations are distributed be- lotype approach. technically impossible to analyze the tween the two parts of the genome? The DNA alphabet consists of only two versions of the approximately three “Because, it can mean, for instance, the the letters ACGT. They stand for the billion base pairs in the human genome difference between cancer and no can- base molecules adenine, cytosine, gua- separately. It simply would have been cer,” she says. “If there are two muta- nine and thymine. Around 90 percent too labor- and cost-intensive. tions – for example, of the BRCA1 risk of the genetic differences between peo- gene associated with breast cancer – ple consist of sites where one letter of GENETIC MAKE-UP IN DUPLICATE they need not necessarily cause the dis- the genetic code – that is, one base – ease.” There are two possibilities: the was replaced by another one. The re- Habits that have become entrenched mutations affect both forms of the gene searchers also refer to these base ex- are difficult to change. “Until recently, (trans), in which case the chances of changes as single nucleotide polymor- even high-ranking experts thought of developing breast cancer are very high; phisms (SNPs). “Everyone has an aver- the genome as a ‘one-fold’ object, not or they are located on only one of the age of one base exchange every 1,700 a ‘two-fold’ one,” says Margret Hoehe, two chromosomes (cis), so the person letters,” explains Hoehe. head of the Genetic Variation, Haplo- will also have a completely “healthy” types & Genetics of Complex Disease form of the gene. CHANGES IN THE GENETIC CODE group at the Max Planck Institute in Cis or trans? The answer to this Berlin, and the first scientist to se- question can mean the difference be- The information for the production of quence the genome of a human being tween good health or illness – and even proteins from individual amino acids – a German – entirely separately based life or death. It can also raise hope. Af- is contained in the order or sequence on the haplotypes. She analyzed both ter all, a “healthy” form of the gene can of the bases. Thus, for example, the sets of chromosomes completely and at be passed on to the next generation. replacement of a cytosine by a thy- a previously unattained level of detail. A good ten years have passed since mine can lead to the use of a different The approach that she developed with Craig Venter and Francis Collins – ini- amino acid. This can result in the pro- her colleagues to do this was singled tially colleagues and later competitors duction of a malfunctioning protein. out by the journal NATURE as one of the – announced the decoding of the hu- When bases in the control regions of most promising methods of 2011. man genome side by side with Bill Clin- the DNA are exchanged, biochemical “Just a minute, we’ll be ready soon. ton in the Oval Office. The end of igno- processes in the body may be blocked It must be possible ... !” Hoehe is look- rance, as Venter said. What a triumph! or accelerated. ing for space on her large desk for two Once we know the genetic code, we will To sequence the genome, the re- teacups and her visitor’s notes. Not an soon also know the function of all searchers isolate DNA from white blood easy task, as the desk is almost entirely genes. We will understand the origin of cells, shred it using ultrasound, and sort covered with towers of publications diseases and be able to heal them. So the fragments by size. The DNA snip- and data printouts. The researcher has far, so good. pets are then fixed to a surface using Graphic: Art 4 Science 66 MaxPlanckResearch 1 | 12 Library in the freezer: The human genome fragments inserted into bacterial DNA molecules are stored at minus 80 degrees. Each of the aluminum-foil-packed genome libraries originates from one person. The genomes of 100 people fill an entire freezer. small anchor molecules and copied. The reading of the base sequence is car- ried out simultaneously for millions of DNA fragments. Today, it takes just a few days to read a complete genome us- ing a second-generation sequencing machine. “The very latest machines reach a throughput of up to three hun- dred billion bases,” says Hoehe. “The early ones could manage only 900 bas- es.” Billions of these sequence reads are stored on a supercomputer. Then the work on the vast jigsaw puzzle begins: the computer compares the base se- quences of the individual snippets and overlaps them to form bigger pieces un- til the DNA is complete. But how does the software know which piece of the puzzle belongs where? “It constantly compares the base sequence of the snippets with those of the reference sequence,” explains Hoehe, “and this is the critical point.” The human genome of 2001, which all scientists still use as a reference, is an artificial product, a cocktail of the DNA of at least six different people. But each person is unique, so this reference se- quence as such doesn’t exist naturally. It doesn’t reflect the genetic code of any particular living person. This was the intention, but many experts now view it as an error, as this makes it an unre- liable roadmap for exploring the causes of health and disease.