In 1866, Gregor Mendel formulated the laws of inheritance and introduced the concept of the allele as a fundamental unit of heredity (Mendel 1886). He used the “numerical method” to derive statistical rules explaining the pattern of observations made during his experimental work on plant hybridization; this work was carried out in a garden of an Augustinian monastery (Brno, Moravia, present-day Czech Republic) between 1856 and 1865. Unfortunately, Mendel’s publication was missed by the mainstream science of the times, and his laws on inheritance were rediscovered only in 1900 by de Vries, Correns and von Tschermak. In the subsequent 50 years, a number of discoveries were made, laying down the biological foundations of genetics. Thus, in 1902, Walter Sutton suggested that “… the association of paternal and maternal chromosomes in pairs and the subsequent separation during the reducing division … may constitute the physical basis of the Mendelian law of heredity” (Sutton 1902, as quoted in Crow and Crow 2002).¹ The subsequent work established that “genes” do indeed reside on chromosomes (1910), that chromosomes contain DNA (1933) and that genes code for proteins (1941). Then, DNA was purified (1944), its first picture taken with X-ray diffraction (1952), and its 3D structure, a double helix, solved by Watson and Crick (1953; Fig. 2.2).

The next 20 years saw, among other discoveries, the cracking of the genetic code (1966)² and the isolation of restriction enzymes, a key discovery allowing the “cutting and pasting” of DNA. The following 20 years introduced two key methodological advancements, namely an electrophoresis-based method for DNA sequencing (1977) and polymerase chain reaction (1983) that enabled most of the work carried out in the 1990s by the HGP. The first disease-causing gene was identified (1989; cystic fibrosis trans-membrane conductance regulator), and the idea of doing genetic “fingerprinting” based on DNA polymorphisms was put forward (1989).

In 1990, the U.S. National Institutes of Health (NIH) and Department of Energy (DOE), together with their international partners, launched the HGP. Over the next 15 years, and with an annual budget of $ 200 million provided by the NIH and DOE, the HGP’s plan was to map and sequence the 3.2-billion-nucleotide-long genome: creating genetic and physical maps of the human genome, identifying all genes and sequencing the entire DNA (Watson and Jordan 1989). The initial plan for the genetic map envisaged one containing ~1,000 highly informative markers, so-called microsatellites, placed—on average—with an interval of ~2–5 million nucleotides. The physical location of these markers, and genes, had to be specified in real “mile stones” placed on the genome’s road: The plan called for the creation of a physical map to be based on the sequence-tagged sites³; a total of 30,000 of such sites were planned initially. The protein-coding genes were to be identified by synthesizing DNA complementary to messenger RNA, the complementary DNA or cDNA. The plan was to create a library of cDNA clones corresponding to all protein-coding genes in the human genome. At the time, the number of genes in the human genome was unknown, the estimates varying between 35,000 and 100,000 genes (Watson and Jordan 1989; Lander 2011). Finally, the goal of mapping the full DNA sequence of the human genome—that is, the sequence of its 3.2 billion bases—by 2005 was clearly highly ambitious, especially given that the critical breakthroughs in parallel sequencing technology came only after the completion of the HGP (Lander 2011).

A quick look at Table 2.1 shows the impressive achievements of the HGP over its first eight years and its goals for the final five years (Collins et al. 1998). The HGP finished in 2003, two years ahead of schedule. Through the HGP, we learned that the total number of protein-coding genes is much lower than expected (~21,000). The genetic map contained ~3,000 markers in 1994 but, in their 1998 report, Collins and colleagues planned to cover the genome with 100,000 single nucleotide polymorphisms (SNPs) over the next five years.⁴ In the same report, Collins et al. (1998) predicted that “SNPs will be a boon for mapping complex traits such as cancer, diabetes, and mental illness”, “… make possible genome-wide association studies…” and “… permit prediction of individual differences in drug response”.

Since the completion of the HGP, a number of other genome-mapping efforts continue. For example, the International HapMap Project builds maps based on the combination of adjacent SNPs inherited together (haplotypes) and identifies SNPs that “tag” unique haplotypes; it is estimated that the human genome contains about 300,000–600,000 such haplotype-tagging SNPs, when compared with a total of 10 million common SNPs (hapmap.ncbi.nlm.nih.gov/thehapmap.html.en). Other efforts, enabled by the shift of parallel sequencing from the electrophoresis based to optical imaging based, focus on genome-wide epigenomic mapping of variations in chromatic modifications and methylation (Lander 2011).

In summary, genetics started in Mendel’s garden with the application of statistics, continued through the basic discoveries explaining the molecular and cellular mechanisms of the genetic machinery, and culminated in the mapping of human genome sequences and the cataloguing of inter-individual variations in its various features. The impressive achievements of the HGP, vis-à-vis basic knowledge about the human genome, advancements of genotyping technology and the creation of genetic databases: all set the stage for mapping the sources of inter-individual variability of complex traits, including the structural and functional properties of the human brain.

In 1861, Broca suggested in his report to the (French) Anatomical Society that the third frontal convolution of the left frontal lobe is the “seat” of “articulated” (spoken) language (Broca 1861). He reached this conclusion by evaluating the symptoms, and dissecting the brain, of a patient called Tan, a 50-year-old man who died in his (surgical) care, due to gangrene of a leg. The patient had been admitted to the Bicêtre Hospital 21 years previously, a few months after losing the ability to speak—since then, the only words he could utter were “tan, tan” (Text Box 2.3.). Broca performed an autopsy within 24 h of Tan’s death; he concluded that the centre of the pathology was in the posterior part of the third convolution of the left frontal lobe and suggested that this was the site of the original lesion that led Tan to lose his ability to speak, 21 years earlier (Broca 1861).