This study develops a new approach to 'population scanning' for unknown rare variants with high throughout and cost-effectiveness. Melt-MADGE combines the properties of microplate array diagonal gel electrophoresis (MADGE) with a reconfiguration of denaturing gradient gel electrophoresis (DGGE) (using a thermal ramp rather than a urea gradient). It may be the most powerful method yet devised, enabling over 4,000 DNA samples to be scanned by a single investigator per day (4x10x96-well gels) in two 2 litre tanks. I have developed 9 assay amplicons representing MC4R and examined a population sample of 1,100 subjects. Two paucimorphisms were identified (V1031 in 28 subjects and -178A > C in 22 subjects). Anthropometric studies of these variants have the power to detect, for example, BMI effects as little as 0.5 units. Two rare variants were also identified, one previously described (T112M) and one unknown (A87D). BMI of 31.5 in the latter, might point to mild functional effects. In LDLR, which has 18 exons, hotspot exons were scanned in both case collections and unselected population samples. Assays of LDLR exons 3, 4 and 8 were validated in 460 familial hypercholesterolemia cases with known mutations. I then applied the exon 3 assay in several DNA banks representing 9,000 subjects with known cholesterol values and applied 3 exons assays in one DNA bank (n=3,600). In exon 3, I have identified one known mutation, P84S (n=1), also associated with moderate hypercholesterolemia in this subject; and an unknown severe hypercholesterolemia splice mutation 313+1G > A (n=2). In exon 4, only one frameshift mutation was detected by the melt-MADGE method. Around exon 8, I have identified a paucimorphism (n=35) at splice site 1061-8T > C (I found it to be in complete linkage disequilibrium with T7051), and an unknown mutation 1186+11G > A (n=1) and D335N G < A (n=1).