**4. Use of ancestral haplotypes**

Here, we illustrate the potential of sequence analysis, if designed to identify conserved, extended, ancestral haplotypes. The utility depends very largely on the concept behind the analysis. However, it also depends upon the genomic region actually sequenced and whether it is possible to interpret the patterns in the context of the heterogeneous architecture of the genome. Within PFB, there will be a multitude of alternative sequences to compare. In the genome between these blocks, there is much less diversity with long stretches of monomorphic sequence. Thus, the recent fashion for identifying homozygosity [27, 28], without regard to diversity, shifts the focus to less informative regions of the genome. Of course, by way of explanation for the fashion, homozygosity within PFB is much more difficult to find; the most common ancestral haplotypes with frequencies of 0.1 will be homozygous in only 1% of the general population. Until high-throughput NGS became available, it was necessary to examine disease panels or consanguineous families.

The conceptual background is summarised in the following figures which contrast two approaches. *Population genetics* teaches that free recombination effectively prevents the packaging of polymorphism. The reality, designated here as *quantal genomics*, emphasises clustering and conservation of polymorphism. Each haplotype is a specific sequence which regulates expressed genes by *cis, trans* or *epistatic* interaction. The whole sequence is conserved. Linkage disequilibrium, when it occurs, is simply a reflection of this conservation which includes haplotypes with alleles which are relatively common in one haplotype when com‐ pared with others. Each is ancestral, in the sense that they are shared by apparently unrelated families separated by hundreds or even thousands of generations. It follows that the poly‐ morphisms are actively conserved and could not be a consequence of recent mutation.

Some of the implications are illustrated in Figures 4 and 5.

**Figure 4.** Importance of clustering functional genes. Colours represent loci and numbers represent alleles at those loci. On the left is the basis of the infinitesimal model used in population genetics. Loci are biallelic and can be homozygous or heterozygous. Free recombination occurs between loci and alleles segregate independently. On the right, loci are within polymorphic frozen blocks (PFB), shown by alignment of loci. Alleles within PFB segregate *en bloc,* forming haplotypes, which are inherited intact through many generations. Important genes are carried within PFB, conserving their *cis* interactions. Loci within PFB have multiple alleles, allowing for a greater degree of polymorphism clustered within the block. There can be hundreds of ancestral haplotypes for each PFB. *Trans* interactions between haplotypes increase the diversity expressed in the population. The loci shown in green and yellow are outside the PFB and follow a pattern of inheritance similar to population genetics. *De novo* mutations are indicated by asterisk—on the right the mutations occur at loci outside of conserved PFB and will have little if any consequence because truly important differ‐ ences are encoded within PFB. Monogenic diseases or traits are the partial exceptions. On the left, mutations can occur at any loci but are generally assumed to occur at loci that were monoallelic. They may or may not be important, de‐ pending upon frequency, context, repair and heritability. Adapted with permission from ref. [22].

By 1987, it was clearly established that each ancestral haplotype has a specific content of genomic features such as duplications and indels. These too are actively conserved and can themselves be used as signatures for haplotypes of hundreds of kilobases and even megabases. These observations were very difficult to explain in terms of any form of neo-Darwinism, natural selection, random errors or population genetics as taught then and today. Rather, we realised, the genome is not actually homogeneous but partitioned into protected quanta or PFB [17, 22, 26, 29].

**Figure 5.** Modern haplotypes are derived from the deep past—they are ancestral haplotypes.
